Supplementary materials

Supplementary methods

Additional information on surface antigen check

The protein localization status for each gene was assessed qualitatively and quantitatively by
checking the confidence of plasma membrane localization, a 0 to 5 score reported in the Gene Cards
website. All genes codifying for proteins with a confidence score for membrane localization<3
and/or
without extracellular domain and full intracellular proteins were discarded from being potential
targets.

Additional statistical and bioinformatic methods

Genes with more than 20% missing data were removed and only significantly differentially
expressed genes after the SAM analysis were retained. For each subtype, the contrast values for the
significant genes were listed in decreasing order and divided into quartiles. The contrast is the
standardized mean difference between the gene’s expression in a class (a breast cancer subtype in
our case), versus its overall mean expression in the overall dataset.
To evaluate Pearson correlation coefficients, we followed the indications elsewhere reported[1].
Namely, a correlation was perfect and uphill for a coefficient (r) of 1, strong for coefficients of 0.7-
0.9, good for coefficients of 0.5-0.7, moderate for coefficients of 0.3-0.5, weak for coefficients of
0.1-0.3 and not linear for a coefficient of 0.
For the external validation process, Cohen’s kappa was interpreted according to McHugh ML [2].

Validation of target specificity

METABRIC clinicopathological and genomic data from Pereira et al. and Curtis et al.[3, 4] were
downloaded from the cBioPortal website (https://www.cbioportal.org). Within the METABRIC
database, 33/36 of our potential target genes were present and with available Z scores, which are
normalized relative expression levels, used as a surrogate for the mRNA level in gene expression
analyses. Missing genes were CEACAM6, SPNS2 and TMEM86A. mRNA levels for each target
gene were compared among the different molecular and IHC subtypes with multiple ANOVA. With
respect to the assessment of the agreement, it was considered inadequate for Cohen’s kappa<0.60
(weak, minimal or none), moderate for 0.60-0.79 values, strong for 0.80-0.90 values and almost
perfect or perfect for values >0.9-1.00[2].
The 11 genes evaluated in patients’ tissues and cell lines were the following: B3GNT3, CA12,
CACNA1H, CEACAM6, ERBB2, FGFR4, ITGB6, ITPR1, PTGER3, SCUBE2 and TSPAN1. A
multiclass SAM was performed among all cell lines, restricted to the 11 available target genes. We
used the following cell lines: BT474, HCC1974, ZR7530, HCC1569, MDA-MB-453, MDA-MB-
468, MDA-MB-231, T47D, SKBR3 and MCF7. Their respective IHC and molecular subtypes are
reported in Supplementary Fig. 5.

nCounter gene expression analysis and cell cultures

A section of the formalin-fixed paraffin-embedded (FFPE) breast tissue proceeding from 470
patients affected by breast cancer and treated at the Hospital Clinic of Barcelona was examined with
hematoxylin and eosin staining to confirm the presence of invasive tumor cells and to determine the
minimum tumor surface area. At least two 10-μm FFPE slides were used to purify total RNA using
the High Pure FFPET RNA Isolation Kit (Roche, Indianapolis, IN, USA). Macrodissection was
performed in baseline samples to avoid contamination with normal breast tissue, when needed. A
minimum of ~100 ng of total RNA was used to measure the expression of 776 breast cancer-related
genes setting up the Breast 360TM Codeset, using the nCounter platform (Nanostring Technologies,
Seattle, WA, USA). This Codeset included the 50 genes of the PAM50 subtype predictor and 726
additional genes that encompass more than 30 gene expression signatures[5]. Data were normalized
using 5 housekeeping genes and log2 transformed. Intrinsic molecular subtypes were identified
using the research-based PAM50 predictor as elsewhere described[6]. The same Codeset was
applied to RNA proceeding from the breast cancer cell lines available at our laboratory, for further
validation.
The breast cancer cell lines were purchased from the American Type Culture Collection (ATCC,
Manassas, VA, USA). All cell lines were maintained as recommended by the suppliers. All cell
lines were authenticated using Human 9-Marker STR Profile and Interspecies Contamination Test
by IDEXX BioAnalytics. All cell lines tested negative for Mycoplasma contamination. The RNeasy
Mini Kit (Qiagen, Hilden, Germany) was used to extract RNA from cell lines.
Supplementary results
Check for surface targets in ongoing CAR-T trials for breast cancer and main ADC targets in
breast tumors: extended
Once identified the best candidates, we decided to check whether our potential targets had already
been exploited in ongoing/already terminated CAR-T clinical trials and which were the
characteristics of already studied targets and why they were not comprised in our list. On the 11 th
march 2020 we performed a search in the online clinical trials databases www.clinicaltrials.gov and
www.carglobaltrials.com. We found overall 28 CAR-T trials for the treatment of breast cancer, of
which 21 were phase 1 and 7 were phase I-II. Six studies were already terminated (for completion
or suspension due to toxicity) and 14 were reported to be recruiting patients. Fifteen trials were
from USA, 10 from China, 1 from UK, 1 from Malaysia and 1 from Belgium and USA. Of all these
studies, only 5 were specific for breast cancer, and the tested targets were: ERBB2, MUC1, MSLN
(mesothelin), MET and CEACAM5 (CEA). All the other studies comprised at least 2 different solid
tumors and 2 of them were focused on liver metastasis. The remaining targets were the following:
GD2, KLRK1 (protein NKG2D), MS4A1 (protein CD20), EPCAM, CD274 (protein PD-L1), ROR1
and CD133/PROM1 (Supplementary tab. 8). We also searched in PubMed the main ADC targets
in breast cancer in current development and the most promising or already targeted in practice
appeared to be TACSD2 (protein TROP-2), SLC39A6 (protein LIV-1), ERBB2 (protein HER2) and
ERBB3 (protein HER3) [7]. All of these targets were found to be differentially expressed in our
analysis but, with the exception of ERBB2, were not included in our list mainly because were not
among the top 200 most up-regulated genes for any of the PAM50 and IHC subtypes
(Supplementary tab. 9), except for LIV-1, CD133, MSLN and GD2 which were not present in our
target list for different reasons. LIV-1 was in top 200 (position 166 for Luminal A, 110 for Luminal
B and 51 for HR+/HER2-negative) but did not pass the toxicity check in normal tissues (between
65 and 72% ND-L in the 3 normal tissues databases, with a cut-off of 75% for target selection);
CD133 was not found significantly differentially expressed; MSLN had been excluded from our
SAM because we dismissed all genes with more than 20% missing data (41.4% for this gene in our
database); GD2 is a ganglioside codified by multiple genes, so could not be included in our
analysis.

Subtype-specificity validation’s detailed results

Based on our study results, for each molecular or IHC subtype, we attributed to each of the 36
candidate genes a score of 1 if the specific gene was suggested as a potential target for that subtype,
otherwise a score of 0 was assigned (refer to Tab. 2 for subtype-specificity). For example, CA12
was attributed a score of 1 for Luminal A/B and HR+/HER2+/neg. tumors, and a score of 0 for all
other subtypes. Subsequently, we accessed the publicly available METABRIC clinicopathological
and genomic data from Pereira et al. and Curtis et al.[3, 4] (see Supplementary methods). When
mRNA levels for a specific gene resulted to be higher in a subtype compared to the others, we
considered such gene as a confirmed potential target for that subtype, with a score of 1, otherwise a
score of 0 was assigned. When no differences in mRNA levels according to subtype were observed,
a 0 score was assigned to that gene for all subtypes. We then checked the percentage of agreement
with the subtype-specific therapeutic indications provided by our study and the METABRIC
database. We further assessed the agreement with Cohen’s Kappa. Significant differences in mRNA
levels were observed for almost all genes (p<0.001 in all cases), except for ADAM33 and SLC4A5,
that showed no significant different levels according to molecular (p=0.841 and p=0.722,
respectively) and IHC subtypes (p=0.381 and p=0.730, respectively) and SLC23A1, according to
IHC subtypes (p=0.952).
We observed an agreement rate ranging from 76% to 94% with a Cohen’s kappa ranging from 0.34
to 0.84 (p values range: <0.001 - 0.026). Based on these values, the level of agreement was
inadequate only for the HR+/HER2+ subgroup and almost moderate for Luminal A. In all other
cases was strong (HR-negative/HER2+ and TNBC) or moderate (Luminal B, HER2-E, Basal-like
and HR+/HER2-negative). For each discordant gene, when we considered the second subtype in
which it showed its major mRNA levels, the agreement rates were considerably improved. Indeed,
we observed an agreement rate ranging from 91% to 100%, with a Cohen’s kappa now ranging
from 0.71 to 1.00 (all p<0.001). In this case, the agreement became strong for almost all subtypes,
except for HER2-E and Basal-like, where it remained moderate and without variations. Full
agreement rates and Cohen’s kappa values are reported in Supplementary table 10.
Furthermore, we collected gene expression data from 470 patients with breast cancer treated at the
Hospital Clinic of Barcelona, to whom an investigational PAM50 test, based on the Breast 360TM
Codeset, had been previously applied[5]. The test included 11/36 of our potential targets
(Supplementary fig. 4), therefore the percentage of agreement and Cohen’s Kappa estimations
were not efficiently assessable. In fact, the subtype specific target agreement ranged between 55%
and 91% (significant p range: 0.007 – 0.044), but Cohen’s Kappa for Basal-like, TNBC and
HR+/HER2+ were unreliable and results not statistically significant (p=0.875, p=0.875 and
p=0.843, respectively), as like for Luminal B tumors (p=0.197). We then followed the same
procedure previously explained for the METABRIC set and observed an agreement ranging from
91% to 100%, with significant improvements in Cohen’s Kappa, now ranging from 0.74 to 1.00 (p
values range: <0.001 - 0.014). Therefore the correlation became moderate for Luminal B and
became or remained strong/perfect for all other cases, except for Basal-like tumors. For this
subgroup none of the genes contained in the Codeset were comprised among the targets that we had
previously identified for this subtype. Thus a reliable validation could not be obtained. Full
agreement rates and Cohen’s kappa values are reported in Supplementary table 10.
Similarly, the same Codeset was applied to all breast cancer cell lines available in our laboratory at
the IDIBAPS in Barcelona. Cell lines’ IHC and molecular subtypes are reported in detail in
Supplementary fig. 5. Differential gene expression analysis and target genes’ mRNA levels
according to cell lines showed that:
 B3GNT3 was more expressed in 1 Basal-like and 1 HER2-E cell lines, both
HR-negative/HER2+;
 CA12 was more expressed in 3 HER2-E cell lines, 1 of those was TNBC, 1 HR+/HER2-
negative and 1 HR+/HER2+;
 CACNA1H was more expressed in 1 Luminal B and HR+/HER2-negative and 1 HER2-E
and HR+/HER2+ cell line;
 CEACAM6 was more expressed in 4 HER2-E cell lines, 2 of which HR+/HER2+ and 2 HR-
negative/HER2+, and in 1 HR+/HER2-negative and Luminal B cell line;
 ERBB2 was more expressed in the HER2+ cell lines, irrespective of HR status, compared to
the others. One cell line was Basal-like, the others HER2-E;
 FGFR4 was more expressed in 3 HER2-E/HER2+ cell lines and 1 HER2-E/TNBC cell line.
 ITGB6 was more expressed in HER2-E/HR-negative/HER2+ and 1 Basal-like/TNBC cell
line;
 ITPR1 was far more expressed in an HER2-E/TNBC cell line;
 PTGER3 was more expressed in 2 HER2-E cell lines, 1 HR-negative/HER2+ and 1
HR+/HER2-negative;
 SCUBE2 was more expressed in HR+/HER2-negative cell lines, 1 Luminal B and 1 HER2-
E;
 TSPAN1 was more expressed in 4 HER2-E cell lines, 1 of those TNBC, 2 HR+/HER2+ and
1 HR-negative/HER2+.

Additional methods and results references

1. Hazra A, Gogtay N. Biostatistics Series Module 6: Correlation and Linear Regression. Indian J
Dermatol 2016; 61(6):593–601.

2. McHugh ML. Interrater reliability: the kappa statistic. Biochem Med 2012; 22(3):276–282.
3. Pereira B, Chin S-F, Rueda OM et al. The somatic mutation profiles of 2,433 breast cancers
refines their genomic and transcriptomic landscapes. Nat Commun 2016; 7:11479.

4. Curtis C, Shah SP, Chin S-F et al. The genomic and transcriptomic architecture of 2,000 breast
tumours reveals novel subgroups. Nature 2012; 486(7403):346–352.

5. Pascual T, Gonzalez-Farre B, Teixidó C et al. Significant Clinical Activity of Olaparib in a

Somatic BRCA1-Mutated Triple-Negative Breast Cancer With Brain Metastasis. JCO Precision
Oncology 2019; (3):1–6.

6. Prat A, Bianchini G, Thomas M et al. Research-based PAM50 subtype predictor identifies

higher responses and improved survival outcomes in HER2-positive breast cancer in the NOAH
study. Clin. Cancer Res. 2014; 20(2):511–521.

7. Bardia A. Antibody-drug conjugates: present and future. Miami Breast Cancer Conference.
2020.
 Supplementary Tables

Supplementary Table 1. Description of the Significance Analysis of Microarrays results according to subtypes.

IHC SUBTYPES
Descriptive measures HR+/HER2- HR+/HER2+ HR-/HER2+ TNBC
Gene Contrast N (%) Gene Contrast N (%) Gene Contrast N (%) Gene Contrast N (%)
Min MRO 0.00013 - NDUFAF2 2.4313E-05 - FAM167A 5.9328E-05 - USP54 0.00079057 -
Max ESR1 3.82086 - STARD3 7.30657839 - STARD3 14.546888 - CBFB 4.9999896 -
Median AOX1 0.51897 - EIF5A2 0.48409912 - KDM5C 1.16539649 - PLEKHM3 1.72337764 -

25% FAM3B 0.24658284 - SLC12A7 0.21831535 - ISCA1 0.55665026 - C4orf43 0.82319482 -

75% PPP2R5A 0.89374262 - HOXB7 0.8479393 - GUCA1B 2.11279012 - DCBLD2 2.83048151 -
N. genes in first quartile - - 1854 (13.3) - - 1748 (12.5) - - 1554 (11.1) - - 1655 (11.9)
Mean - 0.62279712 - - 0.6036975 - - 1.473924 - - 1.911542 -
PAM50 SUBTYPES
Descriptive measures Luminal A Luminal B HER2-Enriched Basal-like
Gene Contrast N (%) Gene Contrast N (%) Gene Contrast N (%) Gene Contrast N (%)
Min SNAP25 0.00034854 - MRPS26 1.9506E-06 - TMEM200A 0.00061953 - CLEC1A 0.00086328 -
Max FOXA1 6.60389116 - ESR1 7.6403835 - ERBB2 14.9629645 - S100A9 4.99900787 -
Median SSFA2 0.97034611 - NDUFA7 1.10384518 - RAB7L1 1.35904976 - CHN1 1.94945333 -
25% PEG3 0.46710085 - GPRC5C 0.5074746 - C2CD2 0.60829118 - IKBKG 0.93970277 -
75% MAPK3 1.63105665 - PHKA1 1.91648049 - MMP11 2.3869941 - SDHD 3.18140129 -
N. genes in first quartile - - 2027 (15.4) - - 1553 (11.1) - - 1467 (11.2) - - 1438 (10.9)
Mean - 1.143831 - - 1.316864 - - 1.706071 - - 2.112904 -

Legend and caption. Genes with the minimum, maximum and median levels of expression according to each BC subtype. Genes identifying the
beginning of the upper and lower quartiles are also identified. HR: hormone receptors; +: positive; -: negative; TNBC: triple negative breast cancer.
 Supplementary Table 2. First 200 most expressed genes and respective d scores at the Significance Analysis of Microarrays for PAM50 and
Immunohistochemistry-based subtypes.

PAM50 Instrinsic Subtypes IHC Simplified Subtypes

Luminal A Luminal B HER2-E Basal-like HR+/HER2- HR+/HER2+ HR-/HER2+ TNBC
Contras Contras Contras
Gene ID Gene ID Gene ID Contrast Gene ID Contrast Gene ID Gene ID Contrast Gene ID Contrast Gene ID Contrast
t t t
FOXA1 6.60389 ESR1 7.64038 ERBB2 14.96296 S100A9 4.99901 ESR1 3.82086 STARD3 7.30658 STARD3 14.54689 CBFB 4.99999
ESR1 6.36709 FOXA1 7.10779 STARD3 14.50112 ADA 4.99638 C6orf97 3.01610 ERBB2 7.22157 ERBB2 13.93694 HLA.DOB 4.99613
MLPH 6.08343 TIMELESS 6.07637 GRB7 13.83301 S100A11 4.99498 AGR3 2.96179 PGAP3 6.89787 GRB7 13.26151 C22orf23 4.99506
AGR3 5.59090 C6orf211 5.97747 PGAP3 13.63402 MAP2K3 4.99435 GATA3 2.94825 C17orf37 6.22302 C17orf37 13.08742 NUF2 4.99321
C6orf97 5.49681 RACGAP1 5.92645 C17orf37 13.62317 PLS3 4.99212 CA12 2.92915 GRB7 5.87622 PGAP3 13.05418 THOC4 4.99210
TBC1D9 5.37793 SPAG5 5.70240 G6PD 11.86921 SMAP1 4.99000 TBC1D9 2.86981 ORMDL3 5.65620 PSMD3 10.90425 TP53BP2 4.99202
THSD4 5.27910 CCNE2 5.66000 MPHOSPH6 11.85269 DHX38 4.98961 GPR77 2.79755 PSMD3 5.57462 ORMDL3 9.47537 RUNX3 4.99043
CA12 5.26470 ESPL1 5.60859 PSMD3 11.62653 CLIP4 4.98732 DNALI1 2.76888 MED1 4.86597 MPHOSPH6 8.75095 SEH1L 4.98422
GATA3 5.16322 DSN1 5.57930 ORMDL3 11.51768 RNF150 4.98335 THSD4 2.73727 FBXL20 4.57334 MED24 7.76853 C6orf106 4.98396
SCUBE2 5.05829 ATAD2 5.35957 TMEM86A 10.67496 C1orf96 4.97977 FOXA1 2.67442 CDK12 4.49770 G6PD 7.51306 SHFM1 4.98086
NOSTRIN 5.02654 GATA3 5.22680 ABCC2 10.31600 SSB 4.97734 SCUBE2 2.58313 MSL1 4.41808 ABCC2 7.44677 VPS72 4.96961
GPR77 5.01641 FANCI 5.11529 GGCT 9.51333 SLCO4A1 4.97733 ERBB4 2.58286 MED24 4.30498 GLYATL2 7.27223 KIF20A 4.96841
XBP1 5.00446 WDR67 5.11167 ETFA 9.10418 CDC5L 4.97426 MLPH 2.58165 RARA 4.00861 CDK12 7.22093 NCL 4.96196
DEGS2 4.91843 WWP1 5.05796 C2orf54 9.00743 VANGL2 4.97345 RERG 2.56735 CWC25 3.86034 GSDMB 7.01945 TCF19 4.95937
DNALI1 4.86894 DTL 5.05696 MFSD2A 8.70164 PTCH1 4.97204 ANXA9 2.52303 RPL19 3.81252 C2orf54 6.95677 CBS 4.95117
MAPT 4.72332 SLC9A3R1 5.04227 SLC25A18 8.54221 ABI1 4.97144 XBP1 2.48342 LOC90110 3.79094 TP53INP2 6.78421 NXN 4.94818
KCNJ11 4.70198 PLEKHF2 5.03905 NUDT8 8.45389 H2AFX 4.97057 KCNJ11 2.48249 CISD3 3.78356 NANOS1 6.76343 MRPL9 4.94547
ZNF552 4.64994 ZWINT 5.02088 TP53INP2 8.39166 EIF4EBP1 4.97018 GREB1 2.46829 GSDMB 3.73019 S100A8 6.70268 TMEM206 4.94453
SLC44A4 4.63564 EME1 4.95604 GSDMB 8.29456 PDIA5 4.96754 DEGS2 2.46251 PIP4K2B 3.64988 TRPV6 6.62776 CHI3L2 4.94386
TENC1 4.58200 PRIM1 4.95385 SERHL 8.28019 LOC401397 4.96543 MAPT 2.44364 CASC3 3.61268 MED1 6.29318 TOMM40 4.94211
ABAT 4.57593 KNTC1 4.84585 KMO 8.19917 SLC10A3 4.96467 ZMYND10 2.44104 LASP1 3.55943 PPP1R10 6.11527 BID 4.94039
PRR15 4.57298 TOP2A 4.83371 NANOS1 8.14451 RGS2 4.96292 CLSTN2 2.42619 PSMB3 3.52769 KMO 6.05279 GINS4 4.93977
CRY2 4.53791 C17orf28 4.79069 TMEM45B 8.11135 LIMK2 4.96276 RABEP1 2.41548 MRPL45 3.46928 ETFA 6.02496 DAPK1 4.93707
KDM4B 4.53293 CDC25C 4.78647 SERHL2 7.96681 YOD1 4.95918 PGR 2.40713 PCGF2 3.35413 NUDT8 5.97264 TPI1 4.93120
SLC7A8 4.53012 NEK2 4.75481 CDK12 7.89528 AVEN 4.95851 KDM4B 2.39159 EPN3 3.15566 FUT3 5.93042 NUTF2 4.92455
PGR 4.47063 TBC1D9 4.74417 FHOD1 7.86378 PNMA6A 4.95665 ACADSB 2.37316 TMEM49 3.07350 SRD5A3 5.91652 LOC100132215 4.92362
ERBB4 4.45388 C6orf97 4.73726 FGFR4 7.73264 CCHCR1 4.95623 TTC8 2.36969 CDC6 2.95182 DNMT3B 5.91503 TMEM71 4.92244
UBXN10 4.44156 XBP1 4.70646 GLYATL2 7.72082 EIF2B3 4.95507 APH1B 2.36966 C17orf28 2.92491 KYNU 5.87609 NFIB 4.91803
FAM47E 4.41906 TMEM97 4.67639 FUT3 7.66627 KLHL21 4.95468 ABAT 2.36356 PPP1R10 2.86496 S100A9 5.86143 CAD 4.91506
ZMYND10 4.40300 RMND1 4.63292 SRD5A3 7.65703 SAP30 4.95281 BCL2 2.36150 SPDEF 2.85979 C1orf198 5.81286 TEAD4 4.90271
NAT1 4.35757 WDR76 4.61588 PGK1 7.61064 TSPO 4.95234 MYB 2.35378 CREB3L4 2.85667 B3GNT3 5.80173 BCL2A1 4.89072
SPDEF 4.30081 CDC6 4.60921 ENPP3 7.50806 NEK2 4.95111 ZNF552 2.31911 SLC9A3R1 2.84310 CDC6 5.77288 GPC2 4.88903
ANXA9 4.25871 TMEM194A 4.59480 S100A9 7.45098 LAMC2 4.95000 AFF3 2.30477 RPL23 2.84150 ACTR3 5.74135 GCNT2 4.88851
C7orf63 4.23571 MLF1IP 4.58640 IDI1 7.37343 DNMT1 4.94777 CACNA2D2 2.30099 WIPF2 2.83559 PLEKHA8 5.73453 ABCF1 4.88775
LRRC48 4.23470 CENPK 4.57898 IDH2 7.32034 RPS19 4.94581 RUNDC1 2.28282 CYB561 2.77971 SLC35C1 5.68934 GAPDH 4.88312
APH1B 4.22030 CMBL 4.55397 FA2H 7.22133 TNFRSF11A 4.94570 ARSG 2.28140 CLTC 2.74858 GGCT 5.68697 PUS7 4.88213
C10orf32 4.21210 ZNF367 4.48383 ABCA12 7.21930 C21orf70 4.94511 C7orf63 2.27614 TRIM3 2.74114 CDR2L 5.67290 MALL 4.88208
AGR2 4.19685 TPD52 4.47576 KYNU 7.19367 LOC728819 4.94424 NAT1 2.26579 ERGIC1 2.68472 LRRC59 5.65720 NCAPH 4.88009
RHOB 4.17738 SKA2 4.46144 CDC6 7.05212 SUN2 4.94303 WDR19 2.25583 SRCIN1 2.68337 CCNYL1 5.62961 C3orf26 4.87885
C10orf26 4.16236 AGR3 4.44727 SLC31A1 6.94813 SH3BGRL3 4.94292 DNAL1 2.24920 TLCD1 2.66084 TMEM86A 5.62529 PLIN2 4.87327
REEP6 4.13736 ECT2 4.43291 C17orf96 6.94737 ZW10 4.94099 GFRA1 2.24079 CCDC87 2.63804 TTYH3 5.62209 ZNF286A 4.87292
ARSG 4.13060 SRP54 4.43230 SC4MOL 6.91853 CBR1 4.93895 SLC22A5 2.23821 RPL19P12 2.63728 VPS37B 5.59584 NDUFA9 4.87195
C14orf45 4.11874 HELLS 4.42977 MORC4 6.87120 ZNF639 4.93149 AGR2 2.23338 SLC2A10 2.63343 SP6 5.51860 C2CD4D 4.86865
RAI2 4.10502 METTL2A 4.42408 DBI 6.84002 PSMA7 4.93130 DNAJC12 2.22790 PRR15 2.62217 GORASP2 5.51649 PRNP 4.86615
ZBTB4 4.08975 UHRF1 4.42292 NXPH4 6.82754 IL23A 4.93054 UBXN10 2.22260 CUEDC1 2.60612 IDH1 5.46121 HAUS8 4.86478
AFF3 4.06745 E2F7 4.41587 PLEKHA8 6.78981 FGD1 4.92832 FBP1 2.21862 XYLT2 2.58988 PPA1 5.40350 DNMT3B 4.86263
CIRBP 4.05628 TMEM106C 4.41120 EAF2 6.76670 RARB 4.92619 FSIP1 2.20394 GALNT6 2.58317 PPP3R1 5.37103 DGKG 4.86172
BCL2 4.04931 ARL6IP1 4.40452 MED24 6.73526 VLDLR 4.92571 SLC7A8 2.19709 FOXA1 2.54106 SURF4 5.33473 YES1 4.85950
CLSTN2 4.03224 PTGES3 4.38504 C14orf147 6.71458 MRPS17 4.92502 APBB2 2.19608 CANT1 2.53589 PNP 5.27915 RCC1 4.85709
SUSD3 4.01729 PAIP2 4.36779 IDH1 6.68536 ATAD3B 4.92397 SPEF2 2.19272 UBE2Z 2.48541 TARS 5.27149 TMEM65 4.85588
FBP1 3.98684 ANXA9 4.36405 MED1 6.57448 IL8 4.92394 SLC39A6 2.19207 DPP3 2.44319 NRBF2 5.26962 GALNT13 4.85579
BCAM 3.97557 CIT 4.36059 PPP1R10 6.54783 CD83 4.92371 SYTL4 2.17564 SNF8 2.42346 YWHAQ 5.26841 MOGS 4.85105
TFF3 3.96056 DNAJC14 4.35624 GGT1 6.53382 TTC4 4.92368 SUSD3 2.17505 SLC4A8 2.41331 CIAPIN1 5.23266 SLC2A12 4.84786
ACADSB 3.94758 C8orf38 4.33138 C9orf140 6.51590 CLSPN 4.92259 DACH1 2.17179 GPR160 2.40999 RPL19 5.21403 E2F4 4.84550
 MYB 3.93107 AGGF1 4.32797 SUSD2 6.44381 LNP1 4.92106 LMX1B 2.17059 PP14571 2.38852 SHCBP1 5.20100 RPP40 4.84459
BTG2 3.92756 PSMD12 4.32630 SP6 6.44230 SFRS4 4.91940 CASC1 2.16955 TMEM86A 2.38814 MTHFD2 5.18745 INCENP 4.84003
DACH1 3.89795 GINS2 4.31600 RALA 6.41917 DDIT4 4.91726 PRR15 2.16460 SAMD11 2.38611 PSMD1 5.16758 SEL1L3 4.83924
KLHDC1 3.87303 MTDH 4.31282 SLC15A2 6.41580 BATF3 4.91687 TPRG1 2.16180 GATA2 2.38572 SLC4A11 5.14608 ZSWIM4 4.83831
C5orf36 3.87137 PPIL5 4.30197 GGTLC2 6.40079 UPF2 4.91516 FAM47E 2.14552 MLPH 2.38200 SPRY4 5.14039 LOXL4 4.83567
SPEF2 3.86462 KIAA0101 4.27681 CDR2L 6.40011 C7orf30 4.91495 SLC44A4 2.13698 RHOB 2.36558 CASP3 5.11035 FAM72D 4.83519
TMEM25 3.85698 FANCD2 4.27633 C7orf68 6.37371 CTCFL 4.91413 ANKRA2 2.12477 BCAS1 2.35825 PSMD14 5.09789 FAM49A 4.83517
GREB1 3.84276 TMPO 4.27507 SLC35C1 6.34409 RNF122 4.91227 NOSTRIN 2.12086 CCDC125 2.35410 CAMK2G 5.09615 PML 4.83008
PHYHD1 3.84086 INTS2 4.25080 DUSP10 6.34234 CD97 4.90847 P4HTM 2.12078 MLLT6 2.35339 MORC4 5.06556 C15orf23 4.82837
RABEP1 3.83740 CCDC43 4.23753 DLG3 6.23731 HYOU1 4.90729 LONRF2 2.11633 SLC39A11 2.34963 ITGB6 5.05641 DZIP1 4.82821
RUNDC1 3.80581 MSI2 4.23634 NRBP1 6.21971 MAST1 4.90301 C9orf116 2.11487 TOM1L1 2.34298 MSL1 5.05102 MAP4K4 4.82445
C20orf103 3.79770 SLC22A5 4.20498 AKR1A1 6.18549 C21orf122 4.89988 RTN4RL1 2.10630 TOB1 2.31816 PERP 5.04563 CDK16 4.81945
INPP4B 3.79607 AGR2 4.19246 RAB3D 6.17566 SLC35C1 4.89964 ZBTB4 2.10623 SCARB2 2.29331 MFSD2A 5.03185 YRDC 4.81657
SIDT1 3.78914 CA12 4.18241 FAM111B 6.14470 BTF3L4 4.89921 C5orf36 2.10135 NEK8 2.28410 C17orf96 5.01042 MORC2 4.81491
MPHOSPH1
CASC1 3.76556 DHFR 4.17496 SEC16A 6.14082 AP2M1 4.89915 KLHDC1 2.09819 WFS1 2.27620 4.99089 PCDHB9 4.81300
0
RAPGEF3 3.74680 PIP4K2C 4.17019 ABCC11 6.14035 NUP88 4.89762 ZNF396 2.08911 IDI1 2.27044 NAMPT 4.98990 ADD2 4.81218
C4A 3.73850 LARP4 4.16507 GGT3P 6.14009 CD82 4.89422 C10orf32 2.08370 SUPT6H 2.25913 SLC15A2 4.98798 OGFRL1 4.81123
KIF13B 3.73739 ATP6V1C1 4.16404 SLC25A5 6.11493 MIR17HG 4.89413 C14orf174 2.07624 XBP1 2.25870 HMGCS1 4.98037 MAMLD1 4.81076
SPARCL1 3.73359 RNF139 4.15605 LRRC59 6.11311 MYBBP1A 4.89247 PHF15 2.07083 NCRNA00176 2.24784 ENPP3 4.96763 WDR12 4.80941
C9orf98 3.72858 CPT1A 4.14581 ERO1L 6.09419 WDR91 4.88937 C14orf45 2.07047 HEATR6 2.24427 NXPH4 4.96527 NAE1 4.80837
CYBRD1 3.72705 AZIN1 4.13267 AKT1 6.08250 E2F5 4.88930 RALGPS2 2.06923 TM7SF2 2.24121 FAM83A 4.96414 BTBD3 4.80769
PCSK4 3.68372 PRKAG1 4.12623 DAP 6.06137 PSMG4 4.88735 LRIG1 2.05584 POLN 2.23544 ZSWIM4 4.95606 IL20RB 4.80715
ABLIM3 3.68238 YWHAB 4.10986 ACSL1 6.03557 B4GALNT1 4.88674 CELSR1 2.05251 PHB 2.23383 MMP15 4.94801 ST14 4.80643
ANKRA2 3.67994 TMEM68 4.10943 SPDEF 6.02000 ADM 4.88086 IVD 2.04294 LRRC59 2.22008 C15orf39 4.94226 PGM1 4.80468
NEK10 3.67782 BRCA1 4.10000 QPRT 6.00722 ZNF74 4.88078 CXXC5 2.03909 CEACAM6 2.20800 SLC35B1 4.94008 MCM2 4.80092
FGD3 3.67678 MLPH 4.08676 SRPK3 6.00321 PABPC3 4.87818 SYBU 2.03532 ALDH3B2 2.19735 ACOT9 4.91712 SLC25A19 4.79807
PGPEP1 3.65760 RPAP3 4.08378 C9orf152 5.99745 MLLT11 4.87337 LRRC48 2.03481 TSKU 2.19277 GPR126 4.88304 MAP7D3 4.79633
STK32B 3.63847 PTPN1 4.06204 HMGCS1 5.99223 TCF7L2 4.87330 C5orf30 2.02561 ARHGAP8 2.18964 MALL 4.88284 PNO1 4.79491
BBS1 3.63425 FSIP1 4.05277 PSMD14 5.98519 C10orf2 4.87006 CYB5D2 2.01898 STARD10 2.18713 RASGRF1 4.83474 MTPAP 4.79408
 TPRG1 3.62374 KIAA0406 4.05138 C15orf39 5.98171 PPP1R8 4.86750 PREX1 2.00269 PPP1R9B 2.18085 TMEM65 4.82487 NCK1 4.79356
TTC8 3.62249 C17orf58 4.04152 AIFM1 5.95693 SMARCB1 4.86581 TMEM25 2.00204 EME1 2.17845 SLC25A13 4.82019 GPRIN2 4.78962
KIF12 3.61683 FAM111B 4.03751 CAP1 5.94930 NUP160 4.86329 TFF3 1.99255 TP53INP2 2.16253 SLC37A1 4.81882 RIN3 4.78427
C9orf116 3.61521 CLTC 4.03454 RASGRF1 5.93665 AARS 4.86111 MAP3K12 1.99136 C4orf34 2.14307 SC4MOL 4.81541 C3orf58 4.78210
LRRC17 3.60761 RFC5 4.02493 WSB2 5.92347 DDX18 4.85782 C12orf72 1.98964 BLVRB 2.14279 RALA 4.81462 PLCH1 4.78023
CALCOCO1 3.60435 CSE1L 4.02103 TBC1D24 5.88390 CCDC59 4.85468 NUDT12 1.98916 CMBL 2.14083 DAP 4.80801 LOC100129637 4.77760
EVL 3.60337 LASS6 4.01921 SLC37A1 5.88182 RCN2 4.85408 ADCY9 1.98363 SYNGR2 2.13407 MICAL3 4.79159 ATP6V1E2 4.77445
CELSR1 3.59550 FLVCR1 4.01117 MVK 5.87740 SNHG12 4.85339 TLE3 1.98119 PANK3 2.12089 GFOD2 4.78311 NMI 4.77087
CACNA2D2 3.58875 RALGAPA1 4.00394 SDC1 5.84551 TLE1 4.85306 KCNK15 1.97767 ORMDL2 2.11933 HIF1A 4.78033 BMS1 4.77072
WDR19 3.58102 HSPA9 4.00308 SURF4 5.84484 PSMD14 4.85078 GLI3 1.97715 INPP5J 2.11777 RRM2 4.74949 S1PR2 4.77070
C4orf32 3.56744 C8orf76 3.99737 PSMD5 5.81033 FARSB 4.84943 TMC4 1.97255 LOC100144603 2.11589 DTX4 4.74566 UBE2S 4.76805
PHF15 3.56243 NFS1 3.99338 NEK6 5.79533 WDR53 4.84855 CCDC103 1.96848 METTL2A 2.10412 UBE2D1 4.74038 OSBPL3 4.76794
INPP5J 3.56055 TERF1 3.99113 FAM83A 5.79489 JMJD6 4.84720 GAMT 1.96806 P2RY2 2.10144 SPNS2 4.72091 C1GALT1 4.76105
SCN4B 3.55821 C12orf66 3.97900 PGD 5.75794 PTGFR 4.84558 FAM63A 1.96782 ALDH8A1 2.10118 FHOD1 4.71380 GABRE 4.76100
TGFB3 3.55154 KIF20B 3.97791 RNF114 5.74605 BOLA3 4.84483 FAM198B 1.96699 CRADD 2.09462 TES 4.70629 LOC100302401 4.75967
APBB2 3.54596 TMED10P1 3.97656 CCDC6 5.70485 WDR3 4.84254 C6orf211 1.96369 GPRC5C 2.09260 NUDT15 4.70069 CALR 4.75739
SLC22A5 3.54546 MNAT1 3.97180 ACPP 5.69883 PRMT1 4.84158 SALL2 1.96050 ACACA 2.08758 SLC31A1 4.70025 DIAPH3 4.74801
DNAJC12 3.53706 ANKRD32 3.96614 MMP1 5.67881 MCTP2 4.83971 PARD6B 1.95901 MMP11 2.08500 KRT7 4.69695 FAM89A 4.74739
ZNF763 3.53453 PARD6B 3.96395 RND1 5.65472 HSP90B1 4.83920 ZNF703 1.95644 CTNNA1 2.07410 TRIM26 4.66214 TACC3 4.74590
CCDC96 3.53444 ARFGEF1 3.96162 COL13A1 5.64117 KHDC1 4.83911 CPEB2 1.95350 USP32 2.07287 TMSB10 4.65771 REXO2 4.74109
KIAA1370 3.52679 GNPNAT1 3.95804 PITPNC1 5.63622 C16orf87 4.83875 FBXL17 1.94669 RPS6KB1 2.07228 DBI 4.65484 CPSF3 4.73740
P4HTM 3.52446 ASF1B 3.95295 CYB561 5.63406 DUSP22 4.83235 BCAM 1.94444 PTRH2 2.06551 FAT1 4.65283 KDM2B 4.73574
CHRD 3.52226 NSF 3.93253 GGCX 5.63382 COL4A4 4.83191 INPP5J 1.93968 TANC2 2.05901 FBXL20 4.64144 MRTO4 4.73442
IGFBP4 3.51923 MCM8 3.92008 PAX9 5.63094 EBNA1BP2 4.83121 GIN1 1.93733 STRADA 2.05816 PSMD7 4.64079 IQCG 4.73389
C5orf53 3.51874 AAGAB 3.90803 GCH1 5.61681 ZBTB5 4.82910 KIAA1370 1.93176 EZR 2.05603 LIMK1 4.63697 CENPL 4.73200
PDGFD 3.51728 BRIP1 3.90568 CBR3 5.60976 ETV4 4.82877 KLHDC2 1.92909 RAG1AP1 2.05276 CKAP4 4.62386 PKP1 4.72875
ABCG2 3.51361 SLC39A6 3.90520 C14orf145 5.60039 TRMT6 4.82847 LRRC46 1.92806 ABCA12 2.04926 WSB2 4.62036 EIF5AL1 4.72337
CBX7 3.50522 RPRD1B 3.89608 ZWINT 5.59223 TATDN1 4.82576 KIAA0141 1.92626 COL10A1 2.04924 IDI1 4.60931 SRF 4.72261
DNAH7 3.50439 ESCO2 3.89300 GCHFR 5.58407 ADCY7 4.82048 TIGD6 1.92327 MB 2.03963 SUSD2 4.60909 SLC35F2 4.72213
PGM5 3.49773 POLR2K 3.88611 GRAMD2 5.58294 HNRNPD 4.82036 GLS2 1.92307 PRR15L 2.03769 IL8 4.60802 PAPD7 4.72186
MEIS3P1 3.49705 AMZ2 3.88246 KRT7 5.56347 METTL4 4.81633 MAGED2 1.91935 SMARCE1 2.02755 ARPC5L 4.59345 ALG3 4.71734
RERG 3.49563 KIAA0196 3.87407 HIF1A 5.55615 FAM176A 4.81608 FAM134B 1.91629 LOC222699 2.02556 OPN3 4.58626 ARHGEF9 4.71538
RSPH1 3.49310 PARP2 3.86815 SPAG5 5.55449 CLDN1 4.81338 LZTFL1 1.91617 TOP2A 2.02345 COX18 4.57662 ATAD3A 4.70934
ZCCHC24 3.47857 SFRS1 3.86264 ITGB6 5.54801 ESPL1 4.81218 INPP4B 1.91576 MRPL27 2.01915 DUSP10 4.57621 KIF23 4.70898
LMX1B 3.47754 ATAD5 3.85869 CCNYL1 5.54626 TOMM34 4.81161 C9orf98 1.91436 PXN 2.01400 FOLH1 4.57337 MPHOSPH10 4.70763
SEMA3G 3.46094 POLE2 3.85555 RPL19 5.53952 GRK6 4.80857 WWP1 1.91404 APPBP2 2.01255 AGFG1 4.56755 GGH 4.69611
CX3CR1 3.45955 SPDEF 3.85524 GALNT7 5.52218 DCAF4 4.80494 NOVA1 1.91199 DCAF4L1 2.00585 GRAMD2 4.56183 MRPL47 4.69542
LRIG1 3.45134 C3orf67 3.85506 PIP5K1B 5.51134 EIF3E 4.80386 STC2 1.91079 SDF2 2.00402 NRBP1 4.54571 MSH6 4.68595
PTPRT 3.44954 TRIM37 3.85042 UFD1L 5.48936 HCG11 4.80325 PCBD2 1.91051 AMZ2 1.99648 NKD1 4.54042 TIMM44 4.68588
RNASE4 3.44621 ZNF252 3.84670 PPA1 5.48774 SLAIN1 4.80280 CMYA5 1.91019 SEC16A 1.99418 PITPNM3 4.53598 FAM100B 4.68577
CHAD 3.44497 MRPS23 3.84419 AP1B1 5.48289 PCBP3 4.79861 DNAH7 1.90755 FA2H 1.98411 PPP1R1B 4.51938 LOC100190939 4.68556
CMYA5 3.44485 DARS2 3.84186 TMEM132A 5.45612 CSNK2B 4.79685 FAM174A 1.90544 RND1 1.97978 C14orf147 4.51713 U2AF1 4.68406
GFRA1 3.44081 SLC16A6 3.83810 ATP13A4 5.45427 INTS10 4.79590 EVL 1.90377 DRP2 1.97482 RNF114 4.49526 MRPS9 4.68344
SYTL4 3.43497 THSD4 3.83686 PSMD1 5.44890 TMEM117 4.79451 SIDT1 1.90194 KRT18 1.96705 COL13A1 4.49360 CXCL16 4.68286
FSIP1 3.43180 CENPQ 3.83469 TRIM62 5.43937 ZNF532 4.79429 STK32B 1.89800 ENPP1 1.96646 ASS1 4.48390 SNRPA 4.67715
TIGD6 3.42181 TMBIM6 3.83365 P4HA1 5.43552 RDX 4.79321 TCTN1 1.89572 THRA 1.96304 CCDC6 4.47508 ABCC10 4.67318
BBS5 3.42128 PRR15 3.82658 TARS 5.43172 WDR46 4.79090 DAZAP2 1.89284 SLC44A4 1.95666 FA2H 4.46776 SF3B3 4.67029
SUOX 3.41752 HMGB2 3.81022 GOT1 5.43073 CIT 4.79084 KIF12 1.89273 CFL1 1.95526 ABCC3 4.45441 FAM72A 4.67000
TSPAN1 3.40431 GFRA1 3.80906 CASP3 5.42826 CABLES2 4.79008 NXPH3 1.89206 FGFR4 1.95318 TDO2 4.43771 UBA2 4.66612
TADA2B 3.40146 EAF1 3.80740 TLE1 5.40916 CYP26B1 4.78988 RAI2 1.89040 PRKAG1 1.95313 ENTPD2 4.42630 WARS 4.66300
FAM174A 3.39488 NKAIN1 3.80673 ASCC2 5.39395 CCNC 4.78395 CMBL 1.88876 LLGL2 1.95088 DUSP6 4.41845 FOLH1 4.66101
CXXC5 3.39338 RAD21 3.80529 ATP6V0D1 5.36926 SSU72 4.78223 CCDC74B 1.88506 LASS6 1.94208 SLC25A18 4.41799 GINS3 4.66022
IFT140 3.39145 CASC5 3.79875 TDO2 5.36836 SEMA5B 4.78058 VAV3 1.88336 PPIL2 1.94161 TMEM189 4.41666 C1orf198 4.66013
C3orf18 3.39002 MYBL1 3.79830 SLC4A5 5.36766 FAM83B 4.77816 BHLHE40 1.88099 RSAD1 1.93339 GPR56 4.41606 KRT23 4.65412
TMC4 3.38878 SLMO2 3.79473 PAPSS2 5.32784 QKI 4.77600 MKL2 1.87878 RANBP9 1.93179 KDELR2 4.41541 CCDC90A 4.65284
ANKRD42 3.38289 CLSTN2 3.79264 AMACR 5.32193 TIPIN 4.77551 TMEM144 1.87693 CA12 1.92826 PEX13 4.41295 RTKN 4.65123
GPR160 3.37232 RDM1 3.78966 CRAT 5.30200 GCSH 4.77537 RHOB 1.87628 FTSJ3 1.92813 TTLL7 4.41231 PSMD7 4.65058
SDPR 3.36867 RDH16 3.78780 COMT 5.30015 CEP152 4.77480 C4orf32 1.87386 CRAT 1.92311 CDK8 4.41047 MYLK4 4.64868
WDR93 3.36574 WDHD1 3.77497 SLC4A11 5.29548 GPR84 4.77423 TENC1 1.87127 ABCC11 1.91759 NSUN2 4.40252 MRPS22 4.64780
FAM161B 3.36319 DNALI1 3.77289 C19orf23 5.28496 MRPL4 4.77106 SPDEF 1.87043 TNFAIP1 1.91515 ZNF124 4.40228 LAD1 4.64694
FAM198B 3.35342 PSMA6 3.75500 GORASP2 5.28314 DEF8 4.76831 CPLX1 1.86660 NME1 1.91200 COQ9 4.40069 KHSRP 4.64638
PTGER3 3.34919 AFF3 3.75095 TNFAIP1 5.26214 LOC284837 4.76698 ZNF763 1.86456 TRAF4 1.91096 ACSL1 4.38120 KRT81 4.64388
TMBIM4 3.34879 TLK2 3.74742 STX1A 5.24685 PARVB 4.76632 IRS1 1.86429 RAPGEFL1 1.90732 PGK1 4.37884 CALB2 4.64088
KIAA0141 3.34635 DENR 3.74029 TRIM26 5.23352 NHEDC2 4.76295 IFT140 1.86111 AATF 1.90628 CCT5 4.37468 CECR7 4.63929
FBXO36 3.34286 EBAG9 3.73897 LOC100134229 5.23061 CDK18 4.76205 ZNF442 1.85873 PTPLAD1 1.90626 SHMT2 4.36847 ADAT2 4.63773
MYH11 3.34226 C16orf75 3.73869 ALDH3B2 5.23039 SLC7A1 4.76165 ANKRD42 1.85388 ESRP2 1.90532 LOC441089 4.36294 PPP2R5D 4.63512
CPEB2 3.34059 UBXN2B 3.73682 CALM1 5.22932 APP 4.76012 C3orf18 1.85161 SLC25A1 1.90464 PSMD5 4.34803 CNTNAP3 4.63430
IVD 3.32575 TOPBP1 3.73257 HMGB3 5.22727 HMGB2 4.75999 TAPT1 1.85094 DHRS13 1.90139 LAD1 4.34360 CTU2 4.63377
DNAH5 3.32492 CDK2 3.73177 CHN1 5.22726 AARS2 4.75846 SKP1 1.85031 PIGS 1.89167 FAM111B 4.34199 SHMT2 4.63024
ALAD 3.31616 FAM91A1 3.72530 C17orf28 5.21830 PLTP 4.75791 DCTN4 1.84642 CPT1A 1.88824 STX1A 4.34082 KIN 4.62927
CYP21A2 3.31442 STAU2 3.72066 SLC25A1 5.21614 CPSF4 4.75421 MAST4 1.84512 GGCT 1.87960 SLC2A12 4.34007 MICAL3 4.62716
MAGED2 3.31419 STRN3 3.70998 CKAP4 5.21367 SENP5 4.75340 NME5 1.84250 RAB5C 1.87862 KLHL2 4.33545 MASTL 4.62389
STC2 3.31334 DERL1 3.70941 ARPC5L 5.21219 CEP57 4.75017 MCCC2 1.84029 HPX 1.87835 BRD7 4.33527 FEN1 4.61934
CAPN8 3.31324 CRNKL1 3.70838 SUCLG1 5.19636 GPR172A 4.74981 FBXL5 1.83962 ITGA11 1.87702 TLE1 4.33386 USP39 4.61771
CCNDBP1 3.30732 HEATR6 3.70483 GNPNAT1 5.19478 HLA.F 4.74949 PTPRT 1.83857 C15orf59 1.87634 NUTF2 4.32661 C9orf100 4.61642
GAMT 3.30436 RALGAPB 3.69379 KDELR2 5.19415 C7orf13 4.74852 WDR93 1.83496 ABHD15 1.87556 UFD1L 4.32642 FAHD2A 4.61531
DNAL1 3.29943 ARHGAP11B 3.69125 ABCC3 5.18182 MRPL3 4.74803 SLC7A2 1.83418 INPP4B 1.87442 GRAMD1B 4.32297 GTF3C2 4.61439
C2orf55 3.29910 CCDC117 3.68723 EBP 5.17351 KLRG2 4.74758 RSPH1 1.83306 TFF3 1.87117 FOXP4 4.31511 FAM60A 4.61195
BBS4 3.28916 NPEPPS 3.68537 ST6GAL1 5.16329 C6orf129 4.74757 CCDC125 1.83022 PRODH 1.87037 STX3 4.30571 C21orf91 4.60814
TMEM26 3.28138 KLHL12 3.68385 MARS 5.15662 CAMTA1 4.74735 SUOX 1.82706 VPS37C 1.86458 IDH2 4.30040 C1orf38 4.60802
RAB17 3.28039 NOL11 3.68341 CAPN13 5.14747 SNX3 4.74423 SPTBN4 1.82474 CACNA1H 1.86450 C16orf87 4.28634 IDO1 4.60716
FANK1 3.27191 MPHOSPH9 3.68149 UBE2L3 5.14019 GNAI1 4.74167 CCDC74A 1.82225 GATA3 1.86287 TXNDC5 4.28139 S100A2 4.60626
SLC39A6 3.27140 KIAA0182 3.67815 MMP15 5.13777 C21orf45 4.73852 SEPSECS 1.82180 CREB3L1 1.85994 RPL19P12 4.27532 FAM127B 4.60585
COL14A1 3.27092 ARSG 3.67558 DOLPP1 5.13227 EFNA4 4.73662 ABLIM3 1.82134 SLC35B1 1.85992 CPSF3 4.27319 DDOST 4.60418
LONRF2 3.27015 RRM1 3.67310 NAMPT 5.12242 PES1 4.73632 TCEAL1 1.82103 BDKRB2 1.85629 CAP1 4.26850 SLC25A13 4.60208
CACNA1D 3.26836 SQLE 3.67238 NDUFA6 5.12234 MT1L 4.73538 TMBIM6 1.82060 ZNF652 1.85624 ATP1A1 4.26731 TRMU 4.60189
SYBU 3.25848 ORMDL2 3.66904 HRH1 5.11830 LAPTM4B 4.73523 PHOSPHO2 1.81798 C9orf7 1.85372 CCT8 4.26676 WWTR1 4.59867
CYB5D2 3.25345 KPNB1 3.66599 PDCL3 5.08988 ADI1 4.73400 HHAT 1.81726 MSI2 1.85081 HMGB3 4.25804 STEAP3 4.59368
ADAM33 3.25273 YWHAZ 3.66583 GM2A 5.08950 LRP6 4.73201 C5orf53 1.81475 C9orf152 1.84593 CCT6A 4.25628 CCT6A 4.59290
RTN4RL1 3.24611 FBP1 3.66208 C20orf108 5.08850 IPO5 4.73150 CCDC30 1.81330 RAB3D 1.84506 ACTR2 4.25579 IFFO2 4.59200
 MAP3K12 3.23995 LOC100128191 3.66104 PRODH 5.08403 LIMK1 4.73105 SEMA3F 1.81023 NR1D1 1.84340 GGCX 4.24981 ARHGAP22 4.59166
LRRC46 3.23924 KIAA1279 3.65341 HSPD1 5.08309 ARHGAP11B 4.72910 RPH3AL 1.80950 INTS2 1.84165 TMEM214 4.24861 CKS2 4.59014
HHAT 3.23754 RMND5B 3.65240 LONRF3 5.07286 XRCC6 4.72899 C17orf68 1.80948 ABCC5 1.83918 PRKAA1 4.24664 GPRC5B 4.58612
IGFALS 3.23547 C17orf80 3.64564 ABCD1 5.06679 TMPRSS13 4.72816 BBS1 1.80896 SPAG5 1.83622 NDUFA6 4.24556 TTC13 4.58545
ZNF703 3.23368 UTP23 3.64143 GRAMD1B 5.06443 TMEM45A 4.72745 TMBIM4 1.80833 CXXC5 1.83475 SLC4A5 4.23647 H2AFZ 4.58152
BTD 3.22789 PVT1 3.63933 IMMT 5.06419 FOXK2 4.72696 BBS5 1.80709 CACNB1 1.82929 AKR1A1 4.22974 MUC16 4.58128
TRIM8 3.22737 ERGIC1 3.63614 P2RY6 5.05713 ZNF146 4.72649 KIAA1467 1.80517 SIDT1 1.82924 UBE2L3 4.22932 EHBP1 4.57766
SCNN1A 3.22345 ELMO2 3.63089 TTLL7 5.03943 NXT1 4.72372 NEK9 1.80501 LDLR 1.82878 TRAF3IP2 4.22088 GAR1 4.57374
CCDC125 3.22181 IARS2 3.62639 ALDH4A1 5.03861 PDE1C 4.72254 CACNA1D 1.80471 PPAPDC1A 1.82850 PAPSS2 4.21476 ACOT9 4.56975
C16orf71 3.22069 SELT 3.62504 LOC338651 5.03815 SFRS15 4.71748 USP30 1.80235 RPL23P8 1.82805 GALK2 4.21265 ARNTL2 4.56872
C14orf174 3.21891 PTPLAD1 3.62463 TRIB3 5.02861 SIGMAR1 4.71712 BAI2 1.80184 RUSC1 1.82205 SDC1 4.20787 GTPBP2 4.56828
PALM 3.21608 USP32 3.62416 CXorf26 5.02466 MYO9B 4.71699 C2orf77 1.79954 ALDH4A1 1.82196 UCHL3 4.20554 VSNL1 4.56820
LRTOMT 3.21209 TSPAN13 3.61980 CCNE2 5.02322 GLG1 4.71485 NEK10 1.79936 DALRD3 1.81911 CCBP2 4.20450 PTMA 4.56382
TCEAL1 3.21036 SRXN1 3.61569 CREB3L4 5.02276 FOXK1 4.71305 BBS4 1.79904 ERAL1 1.81800 PLCB4 4.20393 WIPF3 4.56372
OSCP1 3.20399 CEP290 3.60990 SCARB2 5.02023 SMNDC1 4.71293 NBR1 1.79795 TRIM37 1.81789 USP39 4.20204 SNRPC 4.55922
CCDC30 3.20272 EXOC6 3.59114 MYO18A 5.00193 SH3BP2 4.71112 CREBL2 1.79793 SLC23A1 1.81741 ABLIM1 4.19914 CHST6 4.55913
NISCH 3.20208 FAM84B 3.59087 IL13RA1 5.00090 TGIF2 4.70846 CCDC96 1.79413 MRPL49 1.81634 CYCS 4.19871 CCNB1IP1 4.55433
C10orf79 3.20135 CPNE3 3.58868 UCP2 4.99175 C1orf128 4.70757 TTC39A 1.79146 TUBD1 1.81611 UBE2A 4.19756 ARPC5 4.55400
NUDT12 3.19925 NUBPL 3.58669 FBXL20 4.99053 GFOD1 4.70679 LRTOMT 1.79002 KRT8 1.81539 CHML 4.19308 AKIRIN2 4.55253
OGN 3.19913 VAPB 3.58058 EPN3 4.98173 MRPL51 4.70622 CCNH 1.78924 NQO1 1.81257 IWS1 4.18846 LIPG 4.55096
WFS1 3.19795 C17orf75 3.57906 PPP3R1 4.98136 RTN4IP1 4.70537 FAM114A2 1.78339 EAF2 1.80986 CEL 4.18759 CCDC99 4.54907
GTF2IRD2P1 3.19761 RPS6KB1 3.57725 ANKRD37 4.97933 PPAN 4.70512 BTG2 1.78290 GPRC5A 1.80946 MYO1B 4.18135 PNP 4.54815
EFCAB6 3.19715 L2HGDH 3.56789 AK3L1 4.97782 RASGRF1 4.70474 ITPR1 1.78250 N4BP3 1.80842 PIP5K1B 4.17487 GBP1 4.54754
NEK11 3.19191 NCOA3 3.56478 DHTKD1 4.96457 RTKN2 4.70324 IFT88 1.78087 ATG16L1 1.80787 MAPK6 4.16984 HSPC159 4.54626
ZNF442 3.18283 LARP1 3.55602 SPRED2 4.95761 KCNC4 4.70116 FRY 1.77907 TBC1D3 1.80737 RAB1A 4.16917 STOML2 4.54321
FAAH 3.18137 MTHFD1 3.55327 LGMN 4.94844 LOC441666 4.70075 PRRT3 1.77270 NRK 1.80712 HEATR3 4.16144 ZCCHC18 4.54258
NTN4 3.18037 C8orf83 3.55258 SLC35B1 4.94564 LOC727896 4.70026 CHAD 1.77227 BZW2 1.80655 ACTR1A 4.15926 FIGN 4.54050

Legend and caption. HR: hormone receptors; +: positive; -: negative; TNBC: triple negative breast cancer.
Supplementary Table 3. List of potential candidate genes with membrane localization
confidence score.

Gene name Ensembl ID Confidence score

ABCC5 ENSG00000114770 5
ABCG2 ENSG00000118777 5
ACADSB ENSG00000196177 1
ACPP/ACP3 ENSG00000014257 5
ADA ENSG00000196839 5
ADAM33 ENSG00000149451 4
ADCY7 ENSG00000121281 5
ADD2 ENSG00000075340 5
ADM ENSG00000148926 2
AGR3 ENSG00000173467 1
AKR1A1 ENSG00000117448 4
ALAD ENSG00000148218 2
ALDH3B2 ENSG00000132746 2
ALDH8A1 ENSG00000118514 1
AMACR ENSG00000242110 5
AMZ2 ENSG00000196704 NA
ANKRD42 ENSG00000137494 2
APP ENSG00000142192 5
ARHGAP8 ENSG00000241484 1
ARHGEF9 ENSG00000131089 4
ARNTL2 ENSG00000029153 1
ARSG ENSG00000141337 2
ASF1B ENSG00000105011 1
ASS1 ENSG00000130707 2
ATP6V1E2 ENSG00000250565 1
B3GNT3 ENSG00000179913 4
B4GALNT1 ENSG00000135454 3
BBS1 ENSG00000174483 5
BCAS1 ENSG00000064787 1
BDKRB2 ENSG00000168398 5
BHLHE40 ENSG00000134107 1
BID ENSG00000015475 2
BTD ENSG00000169814 1
BTG2 ENSG00000159388 2
C12orf66 ENSG00000174206 NA
C15orf39 ENSG00000167173 NA
C15orf59/INSYN1 ENSG00000205363 NA
C16orf71 ENSG00000166246 NA
C16orf87 ENSG00000155330 0
C4A ENSG00000244731 5
C5orf30/MACIR ENSG00000181751 NA
C9orf116 ENSG00000160345 1
C9orf152 ENSG00000188959 NA
CA12 ENSG00000074410 5
CACNA1H ENSG00000196557 5
CACNA2D2 ENSG00000007402 4
CALB2 ENSG00000172137 3
CALR ENSG00000179218 4
CASC1 ENSG00000118307 1
CBS ENSG00000160200 NA
CCDC96 ENSG00000173013 NA
CCNE2 ENSG00000175305 2
CCNH ENSG00000134480 1
CD82 ENSG00000085117 5
CD83 ENSG00000112149 5
CDK2 ENSG00000123374 3
CEACAM6 ENSG00000086548 5
CEL ENSG00000170835 4
CENPQ ENSG00000031691 NA
CHAD ENSG00000136457 2
CHI3L2 ENSG00000064886 1
CHRD ENSG00000090539 3
CIAPIN1 ENSG00000005194 1
CLIP4 ENSG00000115295 NA
CLSTN2 ENSG00000158258 4
CMBL ENSG00000164237 1
CMYA5 ENSG00000164309 1
CNTNAP3 ENSG00000106714 4
CPLX1 ENSG00000168993 2
CSE1L ENSG00000124207 2
CTCFL ENSG00000124092 1
CTU2 ENSG00000174177 1
CX3CR1 ENSG00000168329 5
CXCL16 ENSG00000161921 4
CYP21A2 ENSG00000231852 2
CYP26B1 ENSG00000003137 2
DCAF4L1 ENSG00000182308 NA
DGKG ENSG00000058866 4
DHRS13 ENSG00000167536 0
DLG3 ENSG00000082458 5
DNAH5 ENSG00000039139 1
DNAH7 ENSG00000118997 NA
DNALI1 ENSG00000163879 1
DNMT1 ENSG00000130816 2
DTL ENSG00000143476 1
DTX4 ENSG00000110042 1
EAF2 ENSG00000145088 1
EBP ENSG00000147155 5
EFNA4 ENSG00000243364 5
ELMO2 ENSG00000062598 2
ENPP1 ENSG00000197594 5
ENPP3 ENSG00000154269 5
ERBB2 ENSG00000141736 5
ESPL1 ENSG00000135476 3
ESR1 ENSG00000091831 5
EVL ENSG00000196405 2
FA2H ENSG00000103089 2
FAM111B ENSG00000189057 NA
FAM198B/
GASK1B ENSG00000164125 NA
FANCD2 ENSG00000144554 2
FARSB ENSG00000116120 NA
FBP1 ENSG00000165140 2
FGD3 ENSG00000127084 1
FGFR4 ENSG00000160867 5
FHOD1 ENSG00000135723 2
FOLH1 ENSG00000086205 5
FOXA1 ENSG00000129514 2
FTSJ3 ENSG00000108592 1
FUT3 ENSG00000171124 2
GALNT13 ENSG00000144278 1
GAMT ENSG00000130005 2
GATA2 ENSG00000179348 2
GATA3 ENSG00000107485 3
GBP1 ENSG00000117228 4
GCH1 ENSG00000131979 2
GCHFR ENSG00000137880 1
GFRA1 ENSG00000151892 5
GGT1 ENSG00000100031 5
GIN1 ENSG00000145723 1
GINS3 ENSG00000181938 NA
GNAI1 ENSG00000127955 5
GNPNAT1 ENSG00000100522 1
GPR84 ENSG00000139572 5
GPRC5A ENSG00000013588 5
GPRC5B ENSG00000167191 4
GSDMB ENSG00000073605 3
GTF3C2 ENSG00000115207 NA
HEATR3 ENSG00000155393 1
HMGB3 ENSG00000029993 1
HPX ENSG00000110169 3
HRH1 ENSG00000196639 5
HYOU1 ENSG00000149428 2
IDO1 ENSG00000131203 2
IFT140 ENSG00000187535 1
IGFALS ENSG00000099769 1
IGFBP4 ENSG00000141753 2
IL23A ENSG00000110944 2
INTS2 ENSG00000108506 2
IQCG ENSG00000114473 NA
ITGB6 ENSG00000115221 5
ITPR1 ENSG00000150995 5
KCNJ11 ENSG00000187486 5
KIF13B ENSG00000197892 2
KLHL21 ENSG00000162413 1
KMO ENSG00000117009 2
KRT23 ENSG00000108244 1
KRT81 ENSG00000205426 1
LAMC2 ENSG00000058085 3
LDLR ENSG00000130164 5
LIPG ENSG00000101670 2
LONRF3 ENSG00000175556 2
LOXL4 ENSG00000138131 2
LRIG1 ENSG00000144749 5
LRRC46 ENSG00000141294 NA
LZTFL1 ENSG00000163818 1
MALL ENSG00000144063 5
MAMLD1 ENSG00000013619 1
MAP4K4 ENSG00000071054 2
MAPT ENSG00000186868 5
MAST1 ENSG00000105613 3
MAST4 ENSG00000069020 NA
MASTL ENSG00000120539 5
MB ENSG00000198125 2
MCM2 ENSG00000073111 2
MICAL3 ENSG00000243156 4
MMP11 ENSG00000099953 3
MNAT1 ENSG00000020426 1
MORC4 ENSG00000133131 NA
MRTO4 ENSG00000053372 NA
MUC16 ENSG00000181143 5
MYBL1 ENSG00000185697 2
MYH11 ENSG00000133392 2
NAT1 ENSG00000171428 1
NCAPH ENSG00000121152 1
NEK11 ENSG00000114670 1
NEK2 ENSG00000117650 2
NEK6 ENSG00000119408 1
NEK9 ENSG00000119638 2
NKD1 ENSG00000140807 4
NME5 ENSG00000112981 2
NOVA1 ENSG00000139910 1
NRK ENSG00000123572 NA
NSF ENSG00000073969 5
OGN ENSG00000106809 2
OSBPL3 ENSG00000070882 4
P2RY2 ENSG00000175591 5
P2RY6 ENSG00000171631 5
PABPC3 ENSG00000151846 NA
PALM ENSG00000099864 5
PAPSS2 ENSG00000198682 1
PARVB ENSG00000188677 5
PAX9 ENSG00000198807 2
PDGFD ENSG00000170962 3
PERP ENSG00000112378 5
PGM1 ENSG00000079739 2
PGM5 ENSG00000154330 5
PGR ENSG00000082175 3
PIP5K1B ENSG00000107242 1
PITPNM3 ENSG00000091622 1
PKP1 ENSG00000081277 5
PLCB4 ENSG00000101333 2
PLIN2 ENSG00000147872 4
PLTP ENSG00000100979 3
PNP ENSG00000198805 2
POLE2 ENSG00000100479 1
PREX1 ENSG00000124126 5
PRKAA1 ENSG00000132356 3
PRNP ENSG00000171867 5
PRR15 ENSG00000176532 NA
PRRT3 ENSG00000163704 3
PTGER3 ENSG00000050628 5
PTPRT ENSG00000196090 5
QPRT ENSG00000103485 3
RALGAPA1 ENSG00000174373 1
RALGPS2 ENSG00000116191 3
RCN2 ENSG00000117906 1
RDH16 ENSG00000139547 1
RDX ENSG00000137710 5
REEP6 ENSG00000115255 2
RERG ENSG00000134533 3
RIN3 ENSG00000100599 1
RNF114 ENSG00000124226 4
RPH3AL ENSG00000181031 1
RRM2 ENSG00000171848 2
RSPH1 ENSG00000160188 1
RTKN2 ENSG00000182010 2
RUNX3 ENSG00000020633 2
S100A2 ENSG00000196754 3
S100A8 ENSG00000143546 5
S100A9 ENSG00000163220 5
S1PR2 ENSG00000267534 5
SALL2 ENSG00000165821 1
SCUBE2 ENSG00000175356 3
SEMA5B ENSG00000082684 4
SH3BGRL3 ENSG00000142669 1
SKA2 ENSG00000182628 1
SLC16A6 ENSG00000108932 5
SLC23A1 ENSG00000170482 5
SLC2A12 ENSG00000146411 5
SLC31A1 ENSG00000136868 5
SLC35B1 ENSG00000121073 3
SLC4A5 ENSG00000188687 5
SLC7A8 ENSG00000092068 5
SPARCL1 ENSG00000152583 2
SPEF2 ENSG00000152582 NA
SPNS2 ENSG00000183018 3
SPTBN4 ENSG00000160460 4
ST6GAL1 ENSG00000073849 2
STX1A ENSG00000106089 5
SUSD3 ENSG00000157303 5
TACC3 ENSG00000013810 2
TBC1D3 ENSG00000274611 NA
TBC1D9 ENSG00000109436 NA
TDO2 ENSG00000151790 3
TEAD4 ENSG00000197905 2
TFF3 ENSG00000160180 3
TIMELESS ENSG00000111602 1
TIPIN ENSG00000075131 NA
TLE3 ENSG00000140332 2
TM7SF2 ENSG00000149809 5
TMEM132A ENSG00000006118 3
TMEM45A ENSG00000181458 3
TMEM71 ENSG00000165071 3
TMEM86A ENSG00000151117 3
TMEM97 ENSG00000109084 5
TNFAIP1 ENSG00000109079 1
TPRG1 ENSG00000188001 0
TRIB3 ENSG00000101255 4
TRIM3 ENSG00000110171 1
TRPV6 ENSG00000165125 5
TSPAN1 ENSG00000117472 5
TTC39A ENSG00000085831 NA
TTYH3 ENSG00000136295 5
UBE2S ENSG00000108106 3
WDR53 ENSG00000185798 2
WSB2 ENSG00000176871 NA
YRDC ENSG00000196449 1
ZNF532 ENSG00000074657 NA
ZNF652 ENSG00000198740 1

Legend and footnotes. NA: not available; ID: identifier

Supplementary table 4. List of final targets, as per SAM subtype specificity, levels of protein expression in breast cancer tissue and toxicity
risk.

TARGET GROUPS LUMINAL A LUMINAL B HER2-E BASAL-LIKE HR+/HER2- HR+/HER2+ HR-/HER2+ TNBC
GROUP A CX3CR1 GFRA1 FRFR4 EFNA4 GFRA1 CACNA1H ITGB6 TMEM71
(M-H protein GFRA1 SLC16A6 HRH1 ITPR1 ENPP1 SLC4A5
expression in BC and KCNJ11 ITGB6 KCNJ11 FRFR4 B3GNT3
ND-L expression in PTGER3 SLC4A5 PTPRT
≥75% tissues in ≥2 PTPRT SCUBE2
normal tissues db) SCUBE2

GROUP B ADAM33 CA12 AKR1A1 - CA12 CA12 AKR1A1 -

(M-H protein CA12 ERBB2 CEACAM6 ERRB2
expression in BC and TSPAN1 ERRB2
ND-L expression in GPRC5A
≥75% tissues only in
the HPA protein db)
GROUP C LRIG1 - TMEM132A ADA LRIG1 SLC23A1 SPNS2 MUC16
(Low protein SUSD3 TMEM86A ADCY7 PRRT3 TMEM86A TMEM86A
expression in BC and CD83 SUSD3
ND-L expression in GPR84
≥75% tissues in ≥2
normal tissues db) 
EXCLUDED TARGETS - - GGT1 CD82 - LDLR MALL MALL
(Low protein SLC31A1 SLC31A1 PRNP
expression in BC and
ND-L expression in
≥75% tissues only in
the HPA protein db) 

Legend and captions. HER2-E: HER2-enriched; HR: hormone receptors; TNBC: triple negative breast cancer; +: positive; -: negative; SAM:
significance analysis of microarray; M-H: medium/high; ND-L: not detected/low; db: database; HPA: Human Protein Atlas.
Supplementary Table 5. Functions and main characteristics of the potential target genes

GROUP A: Strong Candidates

Genes ID Gene extended name Protein type/Function Role in Cancer/Association with breast cancer Therapeutic target References
Overexpression in many cancer types, including
UDP-GlcNAc:BetaGal
breast cancer.
Beta-1,3-N-
N-acetylglucosaminyltransferase Correlation marker of poor clinical outcome in (1, 2)
B3GNT3 Acetylglucosaminyltransfe No
involved in protein glycosylation. cervical cancer.
rase 3
B3GNT3 downregulation enhances cytotoxic T cell-
mediated anti-tumor responses in TNBC.
Calcium Voltage-Gated
A protein in the voltage-dependent Contributes to the effects of an anti-BC therapy
CACNA1H Channel Subunit Alpha1 H No (3)
calcium channel complex. based on electromagnetic fields.
CX3CL1/CX3CR1 axis is involved in the survival,
CX3C chemokine receptor
Receptor for the CX3C chemokine adhesion and migration of tumor cells, including
CX3CR1 1 No (4, 5)
fractalkine. Expressed in T cells. BC.
Potential expression in tumor cells.
Receptor protein-tyrosine kinases
Negative correlation between EFNA4 expression Anti-EFNA4 ADC tested in
Ephrin A4 anchored to the membrane by a (6-8)
EFNA4 and overall survival in BC. a phase I study in TNBC.
glycosylphosphatidylinositol (GPI)
Important for mammary epithelial cell growth. NCT02078752
linkage.
Ectonucleotide
Glycoprotein with phosphatase and
ENPP1 Pyrophosphatase/Phosph Facilitates breast cancer metastasis to the bone. No (9)
phosphodiesterase activity
odiesterase 1
Overexpressed in several tumor types, including
Tyrosine kinase receptor that Monoclonal antibodies,
Fibroblast Growth Factor Her-2 enriched cancers. Linked to tumor growth
regulates cellular pathways involved scFv and CARs against (10-13)
FGFR4 Receptor 4 and apoptosis resistance.
in proliferation, differentiation and FGFR4.
Acquired alterations reported in FGFR4 in Her2-
survival. WO2017049296A1
enriched cancer upon metastatic progression.
Involved in proliferation and survival of tumor Anti-GFRA1 antibodies
GDNF Family Receptor
cells, including BC. patented for the (14, 15)
GFRA1 Alpha 1 GPI-linked and a coreceptor of RET
GFRA1 positivity predicts reduced overall survival treatment of cancer.
and poor response to multiple modes of therapy. EP1863530B1
HRH1 expression correlates with bad prognosis in
Is an integral membrane protein.
Histamine Receptor H1 subtypes of breast cancer.
HRH1 Belongs to the G protein-coupled No (16, 17)
Inhibition of HRH1 enhances therapeutic antitumor
receptor superfamily.
effects.
 Member of the integrin superfamily.
Integrin subunit beta 6 Adhesion receptor that function in Involved in metastatic progression of Her2- (18, 19)
ITGB6 No
signaling from the extracellular enriched tumors.
matrix to the cell
Provides instructions for making a
Inositol 1,4,5-
protein that is part of a channel that
Trisphosphate Receptor
ITPR1 controls the flow of positively - No -
Type 1
charged calcium atoms (calcium ions)
within cells
Potassium Inwardly
Multi-pass membrane protein.
Rectifying Channel Differentially expressed in HCC and predicts poor
KCNJ11 Subunit of an ATP-sensitive No (20)
Subfamily J Member 11 prognosis.
potassium channel.
Induces tumor growth, tumor angiogenesis and
Prostaglandin E Receptor
It is one of four receptors identified resistance to chemotherapy in ovarian cancer. (21-23)
PTGER3 3 No
for prostaglandin E2 (PGE2) Suggested as prognostic marker for favorable
prognosis in BC.
Receptor-type tyrosine-
Receptor protein tyrosine Controversial role in cancer, with both pro- and
PTPRT protein phosphatase T No (24-26)
phosphatase T anti-tumorigenic effects described.
Signal Peptide, CUB
Domain And EGF Like Prognostic marker for favorable prognosis and
SCUBE2 Secreted cell surface glycoprotein No (27, 28)
Domain Containing 2 tumor suppressor.

Member of a family of solute carriers

Solute Carrier Family 16
(SLC). Some SLC16A family members
SLC16A6 Member 6 - No -
play crucial roles in tumorigenesis
and tumor progression.
Solute Carrier Family 4
Member of the sodium bicarbonate Upregulated in breast and colon cancer.
SLC4A5 Member 5 No (29)
cotransporter family
Overexpressed in glioma, where its expression is
Transmembrane Protein
Expressed in immune cells. Unknown associated to PD-1, PD-L1 and TIM-3. Correlates
TMEM71 71 No (30)
function. with short survival in patients with glioma and
glioblastoma. No role found in breast cancer
GROUP B: Moderate Candidates
ADAM33 ADAM Metallopeptidase A disintegrin and metalloprotease Downregulation in TNBC correlates with shorter No (31, 32)
Domain 33 family member, involving cell-cell overall survival and metastasis-free survival.
 and cell-matrix interactions.
Aldo-Keto Reductase Aldehyde reductase, is involved in
AKR1A1 Family 1 Member A1 the reduction of biogenic and - No -
xenobiotic aldehydes
Overexpressed in cancer, including renal and
Zinc metalloenzyme, responsable for
Carbonic Anhydrase 12 breast cancer.
CA12 the acidification of the No (33)
Regulated by estrogen via ERa in breast cancer
microenvironment of cancer cells.
cells.
Overexpressed in many human epithelial and
Member of the CEA family of glycosyl Anti-CEACAM6 antibodies
Carcinoembryonic hematologic malignancies
phosphatidyl inositol (GPI) anchored (NCT03596372)
antigen-related cell Associated with the development of invasive (34-37)
CEACAM6 cell surface glycoproteins. Members CAR-T cells targeting
adhesion molecule 6 breast cancer. Promotes migration and invasion.
of this family play a role in cell CEACAM6 are under
Prediction marker of recurrence after tamoxifen
adhesion. preclinical investigation.
adjuvant
V-Erb-B2 Avian
Erythroblastic Leukemia Monoclonal antibodies
Viral Oncogene Homolog Amplification or over-expression of this oncogene and ADC against HER2,
ERBB2 Glycoprotein with tyrosine kinase
2 (Human Epidermal promotes tumor progression in different cancer > 10 trials with anti-Her2 (38-42)
(HER2) activity.
Growth Factor Receptor types, including breast cancer. CAR-T cells listed in
2) clinicaltrials.gov

G Protein-Coupled
Overexpressed in a number of cancer types. Its role
Receptor Class C Group 5 G protein coupled receptor family C
GPRC5A in breast cancer is controversial, with both pro- No (43, 44)
Member A group 5 member A
and anti-tumorigenic effects described.
Member of the tetraspanins family.
These proteins mediate signal Overexpressed in a number of cancer types, with
transduction events that play a role controversial roles, with both pro- and anti-
TSPAN1 Tetraspanin 1 No (45, 46)
in the regulation of cell tumorigenic effects described. Suggested role as
development, activation, growth and tumor suppressor in breast cancer.
motility
GROUP C: Weak Candidates
Adenosine deaminase mostly located
Inhibition of ADA inhibits breast cancer
Adenosine deaminase in lymphocytes. Its primary function
ADA progression and suppresses migration and No (47)
is the development and maintenance
invasion.
of the immune system.
ADCY7 Adenylate Cyclase 7 Enzyme containing several - No -
transmembrane domain and
 extracellular motifs between TM
loops
Member of the immunoglobulin
superfamily of receptors. Expressed
CD83 Molecule Higher survival rate of patients with CD83+
CD83 in mature dendritic cells and No (48)
infiltrating DCs in breast cancer
involved in the regulation of antigen
presentation.
Probable G-protein Mainly expressed in immune cells.
GPR84 coupled receptor 84 GPR84 activation is involved in the - No -
inflammatory response.
Member of the LRIG family of Cell surface protein that antagonises ERBB
Leucine Rich Repeats and
transmembrane leucine-rich repeat- receptor signalling by downregulating receptor
Immunoglobulin Like
LRIG1 containing proteins. Acts as a levels. No (49, 50)
Domains 1
feedback negative regulator of pan-ERBB negative regulator, intestinal stem cell
signaling by receptor tyrosine kinases marker and tumour suppressor
CAR-T cells targeting MUC-
16 being tested in clinical
MUC16 Mucin 16 (Cancer Antigen Promotes proliferation and inhibits apoptosis in
Mucin extensively glycosylated trials for the treatment of (51-53)
(CA125) 125) breast cancer cells.
ovarian cancer.
NCT02498912
Proline Rich
Proline-rich transmembrane protein
PRRT3 Transmembrane Protein 3 - No -
3
Role in the absorption and
distribution of Vitamin C. Spns2-null
Solute Carrier Family 23
mouse are viable but have decreased
SLC23A1 Member 1 - No
lymphocytes in circulation and
reduction in mature B cells in the
spleen and bone marrow.
Spinster homolog 2 Transporter of sphingosine 1-
SPNS2 - No -
phosphate.
Sushi Domain Containing Promoter of estrogen-dependent cell proliferation
SUSD3 3 Unknown function. and regulator of cell–cell and cell–substrate No (54, 55)
interactions and migration in breast cancer.
TMEM132 Transmembrane Protein protein that is highly similar to the TMEM132D serves as predictor of CD8+ T- No (56)
A 132A rat Grp78-binding protein (GBP). lymphocyte infiltration and as favourable
Negative regulator of programmed prognostic markers in early stage ovarian cancer.
cell death. Expressed in the central
 nervous system.
Transmembrane Protein
TMEM86A 86A Specific hydrolase activity - No -

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Supplementary Table 6. Correlation coefficients for target genes.

GENE ID ADA ADAM3 ADCY AKR1A B3GNT3 CA12 CACNA1 CD83 CEACAM6 CX3CR EFNA ENPP ERBB FGFR GFRA GPR8 GPRC5 HRH ITGB ITPR KCNJ1 LRIG MUC1 PRRT PTGER PTPR SCUBE SLC16A SLC23A SLC4A SPNS SUSD TMEM132 TMEM7 TMEM86 TSPAN1
3 7 1 H 1 4 1 2 4 1 4 A 1 6 1 1 1 6 3 3 T 2 6 1 5 2 3 A 1 A
ADA 1.00 0.14 0.41 0.20 0.21 -0.38 -0.12 0.41 -0.17 -0.23 0.30 -0.35 -0.14 0.12 -0.28 0.41 -0.26 0.26 0.03 -0.44 -0.37 -0.41 0.11 -0.30 -0.20 -0.32 -0.34 -0.42 -0.05 0.12 0.37 -0.16 0.27 0.29 0.00 -0.28

ADAM33 0.14 1.00 0.11 0.05 -0.13 0.26 0.19 0.04 -0.04 0.37 0.06 0.12 0.03 0.02 0.23 -0.16 -0.04 0.27 0.06 0.16 0.25 0.18 -0.16 0.17 0.42 0.25 0.34 0.06 0.06 -0.16 0.37 0.34 -0.03 0.13 0.15 0.15

ADCY7 0.41 0.11 1.00 -0.14 0.21 -0.34 -0.12 0.58 -0.11 0.11 0.02 -0.20 -0.14 0.02 -0.25 0.53 -0.13 0.44 0.13 -0.14 -0.42 -0.28 0.24 -0.40 -0.08 -0.16 -0.28 -0.23 -0.15 -0.06 0.28 -0.21 0.04 0.40 0.01 -0.28

AKR1A1 0.20 0.05 -0.14 1.00 0.05 -0.05 -0.08 0.01 0.05 -0.08 0.34 -0.08 0.10 0.12 -0.11 0.15 -0.13 0.00 -0.03 -0.20 -0.02 -0.02 -0.06 -0.01 -0.08 -0.10 -0.06 -0.19 -0.01 0.22 0.22 -0.01 0.16 -0.02 0.33 0.18

B3GNT3 0.21 -0.13 0.21 0.05 1.00 -0.41 -0.23 0.14 0.10 -0.18 0.22 -0.31 0.04 0.12 -0.45 0.14 -0.12 0.28 0.22 -0.33 -0.45 -0.30 0.34 -0.40 -0.31 -0.37 -0.40 -0.30 -0.16 0.10 0.38 -0.34 0.15 0.39 0.02 -0.23

CA12 -0.38 0.26 -0.34 -0.05 -0.41 1.00 0.41 -0.35 0.21 0.37 -0.30 0.58 0.17 -0.17 0.63 -0.28 0.43 -0.09 0.05 0.60 0.64 0.62 -0.40 0.56 0.58 0.57 0.73 0.65 0.22 -0.22 -0.30 0.60 -0.30 -0.42 0.19 0.60

CACNA1H -0.12 0.19 -0.12 -0.08 -0.23 0.41 1.00 -0.22 0.14 0.08 -0.27 0.32 0.17 0.07 0.36 -0.26 0.28 -0.02 -0.10 0.26 0.37 0.17 -0.32 0.38 0.23 0.16 0.32 0.34 0.12 -0.09 -0.06 0.20 0.06 -0.33 0.13 0.33

CD83 0.41 0.04 0.58 0.01 0.14 -0.35 -0.22 1.00 -0.13 0.13 0.11 -0.23 -0.18 -0.04 -0.22 0.58 -0.18 0.23 0.04 -0.23 -0.36 -0.28 0.25 -0.31 -0.11 -0.16 -0.24 -0.32 -0.13 0.03 0.26 -0.15 -0.03 0.47 0.00 -0.31

CEACAM6 -0.17 -0.04 -0.11 0.05 0.10 0.21 0.14 -0.13 1.00 0.13 -0.11 0.25 0.29 -0.02 0.06 -0.09 0.32 0.14 0.21 0.17 0.21 0.22 -0.07 0.17 0.03 0.17 0.17 0.28 0.02 -0.09 -0.06 0.05 -0.13 -0.14 0.35 0.47

CX3CR1 -0.23 0.37 0.11 -0.08 -0.18 0.37 0.08 0.13 0.13 1.00 -0.17 0.33 -0.03 -0.19 0.26 0.09 0.11 0.12 0.17 0.45 0.29 0.41 -0.11 0.16 0.41 0.46 0.50 0.26 -0.04 -0.39 0.08 0.41 -0.40 0.08 0.20 0.25

EFNA4 0.30 0.06 0.02 0.34 0.22 -0.30 -0.27 0.11 -0.11 -0.17 1.00 -0.27 0.09 0.15 -0.27 0.13 -0.19 0.09 0.20 -0.45 -0.23 -0.17 0.21 -0.25 -0.18 -0.13 -0.25 -0.47 -0.03 0.13 0.30 -0.12 0.26 0.25 0.07 -0.20

ENPP1 -0.35 0.12 -0.20 -0.08 -0.31 0.58 0.32 -0.23 0.25 0.33 -0.27 1.00 0.22 -0.07 0.46 -0.20 0.41 -0.02 0.06 0.50 0.51 0.49 -0.39 0.46 0.41 0.36 0.53 0.54 0.13 -0.10 -0.24 0.33 -0.22 -0.35 0.24 0.44

ERBB2 -0.14 0.03 -0.14 0.10 0.04 0.17 0.17 -0.18 0.29 -0.03 0.09 0.22 1.00 0.31 -0.01 -0.21 0.24 0.12 0.28 0.12 0.17 0.14 -0.18 0.17 0.04 0.01 0.05 0.23 0.13 0.09 0.09 -0.05 0.22 -0.21 0.42 0.19

FGFR4 0.12 0.02 0.02 0.12 0.12 -0.17 0.07 -0.04 -0.02 -0.19 0.15 -0.07 0.31 1.00 -0.18 -0.08 -0.09 0.13 0.01 -0.16 -0.02 -0.23 -0.14 -0.06 -0.21 -0.23 -0.22 -0.17 0.11 0.29 0.19 -0.22 0.47 -0.01 0.25 -0.09

GFRA1 -0.28 0.23 -0.25 -0.11 -0.45 0.63 0.36 -0.22 0.06 0.26 -0.27 0.46 -0.01 -0.18 1.00 -0.29 0.28 -0.26 -0.14 0.42 0.58 0.48 -0.33 0.50 0.50 0.51 0.64 0.47 0.15 -0.15 -0.33 0.52 -0.22 -0.34 0.05 0.41

GPR84 0.41 -0.16 0.53 0.15 0.14 -0.28 -0.26 0.58 -0.09 0.09 0.13 -0.20 -0.21 -0.08 -0.29 1.00 -0.17 0.19 0.09 -0.22 -0.42 -0.27 0.31 -0.29 -0.14 -0.18 -0.23 -0.28 -0.10 -0.02 0.19 -0.10 -0.04 0.29 0.02 -0.21

GPRC5A -0.26 -0.04 -0.13 -0.13 -0.12 0.43 0.28 -0.18 0.32 0.11 -0.19 0.41 0.24 -0.09 0.28 -0.17 1.00 0.06 0.20 0.35 0.30 0.29 -0.18 0.25 0.24 0.17 0.36 0.42 0.05 -0.15 -0.16 0.21 -0.10 -0.26 0.15 0.41

HRH1 0.26 0.27 0.44 0.00 0.28 -0.09 -0.02 0.23 0.14 0.12 0.09 -0.02 0.12 0.13 -0.26 0.19 0.06 1.00 0.37 -0.04 -0.29 -0.14 0.07 -0.31 0.05 -0.11 -0.14 -0.14 -0.11 -0.03 0.41 -0.21 0.08 0.27 0.30 0.01

ITGB6 0.03 0.06 0.13 -0.03 0.22 0.05 -0.10 0.04 0.21 0.17 0.20 0.06 0.28 0.01 -0.14 0.09 0.20 0.37 1.00 0.06 -0.08 0.09 0.03 -0.18 0.04 0.06 0.02 0.00 -0.08 -0.12 0.18 -0.13 0.02 0.12 0.25 0.18

ITPR1 -0.44 0.16 -0.14 -0.20 -0.33 0.60 0.26 -0.23 0.17 0.45 -0.45 0.50 0.12 -0.16 0.42 -0.22 0.35 -0.04 0.06 1.00 0.44 0.57 -0.30 0.37 0.44 0.45 0.54 0.61 0.04 -0.25 -0.25 0.40 -0.38 -0.24 0.12 0.43

KCNJ11 -0.37 0.25 -0.42 -0.02 -0.45 0.64 0.37 -0.36 0.21 0.29 -0.23 0.51 0.17 -0.02 0.58 -0.42 0.30 -0.29 -0.08 0.44 1.00 0.56 -0.44 0.65 0.41 0.52 0.64 0.51 0.18 -0.13 -0.30 0.55 -0.16 -0.42 0.22 0.52

LRIG1 -0.41 0.18 -0.28 -0.02 -0.30 0.62 0.17 -0.28 0.22 0.41 -0.17 0.49 0.14 -0.23 0.48 -0.27 0.29 -0.14 0.09 0.57 0.56 1.00 -0.31 0.42 0.53 0.53 0.60 0.55 0.12 -0.17 -0.24 0.55 -0.43 -0.24 0.19 0.45

MUC16 0.11 -0.16 0.24 -0.06 0.34 -0.40 -0.32 0.25 -0.07 -0.11 0.21 -0.39 -0.18 -0.14 -0.33 0.31 -0.18 0.07 0.03 -0.30 -0.44 -0.31 1.00 -0.38 -0.28 -0.14 -0.33 -0.37 -0.19 -0.06 0.19 -0.24 0.03 0.35 -0.20 -0.31

PRRT3 -0.30 0.17 -0.40 -0.01 -0.40 0.56 0.38 -0.31 0.17 0.16 -0.25 0.46 0.17 -0.06 0.50 -0.29 0.25 -0.31 -0.18 0.37 0.65 0.42 -0.38 1.00 0.30 0.34 0.50 0.50 0.26 -0.09 -0.29 0.44 -0.08 -0.45 0.11 0.40

PTGER3 -0.20 0.42 -0.08 -0.08 -0.31 0.58 0.23 -0.11 0.03 0.41 -0.18 0.41 0.04 -0.21 0.50 -0.14 0.24 0.05 0.04 0.44 0.41 0.53 -0.28 0.30 1.00 0.42 0.63 0.46 0.10 -0.20 -0.06 0.51 -0.32 -0.16 0.09 0.29

PTPRT -0.32 0.25 -0.16 -0.10 -0.37 0.57 0.16 -0.16 0.17 0.46 -0.13 0.36 0.01 -0.23 0.51 -0.18 0.17 -0.11 0.06 0.45 0.52 0.53 -0.14 0.34 0.42 1.00 0.61 0.41 -0.02 -0.33 -0.22 0.49 -0.35 -0.20 0.10 0.38

SCUBE2 -0.34 0.34 -0.28 -0.06 -0.40 0.73 0.32 -0.24 0.17 0.50 -0.25 0.53 0.05 -0.22 0.64 -0.23 0.36 -0.14 0.02 0.54 0.64 0.60 -0.33 0.50 0.63 0.61 1.00 0.54 0.14 -0.31 -0.20 0.60 -0.33 -0.33 0.19 0.53

SLC16A6 -0.42 0.06 -0.23 -0.19 -0.30 0.65 0.34 -0.32 0.28 0.26 -0.47 0.54 0.23 -0.17 0.47 -0.28 0.42 -0.14 0.00 0.61 0.51 0.55 -0.37 0.50 0.46 0.41 0.54 1.00 0.06 -0.15 -0.35 0.43 -0.32 -0.38 0.09 0.42

SLC23A1 -0.05 0.06 -0.15 -0.01 -0.16 0.22 0.12 -0.13 0.02 -0.04 -0.03 0.13 0.13 0.11 0.15 -0.10 0.05 -0.11 -0.08 0.04 0.18 0.12 -0.19 0.26 0.10 -0.02 0.14 0.06 1.00 0.05 -0.10 0.07 0.06 -0.21 0.10 0.08

SLC4A5 0.12 -0.16 -0.06 0.22 0.10 -0.22 -0.09 0.03 -0.09 -0.39 0.13 -0.10 0.09 0.29 -0.15 -0.02 -0.15 -0.03 -0.12 -0.25 -0.13 -0.17 -0.06 -0.09 -0.20 -0.33 -0.31 -0.15 0.05 1.00 0.05 -0.21 0.19 -0.02 0.01 -0.07

SPNS2 0.37 0.37 0.28 0.22 0.38 -0.30 -0.06 0.26 -0.06 0.08 0.30 -0.24 0.09 0.19 -0.33 0.19 -0.16 0.41 0.18 -0.25 -0.30 -0.24 0.19 -0.29 -0.06 -0.22 -0.20 -0.35 -0.10 0.05 1.00 -0.15 0.24 0.43 0.17 -0.19

SUSD3 -0.16 0.34 -0.21 -0.01 -0.34 0.60 0.20 -0.15 0.05 0.41 -0.12 0.33 -0.05 -0.22 0.52 -0.10 0.21 -0.21 -0.13 0.40 0.55 0.55 -0.24 0.44 0.51 0.49 0.60 0.43 0.07 -0.21 -0.15 1.00 -0.34 -0.18 0.05 0.31

TMEM132 0.27 -0.03 0.04 0.16 0.15 -0.30 0.06 -0.03 -0.13 -0.40 0.26 -0.22 0.22 0.47 -0.22 -0.04 -0.10 0.08 0.02 -0.38 -0.16 -0.43 0.03 -0.08 -0.32 -0.35 -0.33 -0.32 0.06 0.19 0.24 -0.34 1.00 0.01 0.10 -0.20
A
TMEM71 0.29 0.13 0.40 -0.02 0.39 -0.42 -0.33 0.47 -0.14 0.08 0.25 -0.35 -0.21 -0.01 -0.34 0.29 -0.26 0.27 0.12 -0.24 -0.42 -0.24 0.35 -0.45 -0.16 -0.20 -0.33 -0.38 -0.21 -0.02 0.43 -0.18 0.01 1.00 -0.13 -0.36

TMEM86A 0.00 0.15 0.01 0.33 0.02 0.19 0.13 0.00 0.35 0.20 0.07 0.24 0.42 0.25 0.05 0.02 0.15 0.30 0.25 0.12 0.22 0.19 -0.20 0.11 0.09 0.10 0.19 0.09 0.10 0.01 0.17 0.05 0.10 -0.13 1.00 0.37

TSPAN1 -0.28 0.15 -0.28 0.18 -0.23 0.60 0.33 -0.31 0.47 0.25 -0.20 0.44 0.19 -0.09 0.41 -0.21 0.41 0.01 0.18 0.43 0.52 0.45 -0.31 0.40 0.29 0.38 0.53 0.42 0.08 -0.07 -0.19 0.31 -0.20 -0.36 0.37 1.00

Legend and captions. The significance of the correlation is not reported.

Supplementary Table 7. Most uphill correlated gene pairs.

 Correlation Quality of the
Subtype Gene pair
coefficient correlation
CA12-SLC16A6 0.32 Moderate
CX3CR1-PTPRT 0.32 Moderate
Luminal A ITPR1-LRIG1 0.33 Moderate
ITPR1-SLC16A6 0.36 Moderate
LRIG1-PTPRT 0.31 Moderate
Luminal B KCNJ11-PRRT3 0.40 Moderate
AKR1A1-SLC4A5 0.31 Moderate
HER2-Enriched HRH1-ITGB6 0.36 Moderate
HRH1-TMEM86A 0.33 Moderate
Basal-like ADCY7-GPR84 0.38 Moderate
CA12-ENPP1 0.31 Moderate
CA12-GFRA1 0.39 Moderate
CA12-ITPR1 0.30 Moderate
CA12-KCNJ11 0.35 Moderate
CA12-LRIG1 0.37 Moderate
CA12-PRRT3 0.32 Moderate
CA12-PTGER3 0.41 Moderate
CA12-PTPRT 0.32 Moderate
HR+/HER2- CA12-SCUBE2 0.56 Good
CA12-SLC16A6 0.41 Moderate
CA12-SUSD3 0.44 Moderate
CX3CR1-ITPR1 0.32 Moderate
CX3CR1-PTPRT 0.43 Moderate
CX3CR1-SCUBE2 0.35 Moderate
ENPP1-LRIG1 0.32 Moderate
ENPP1-SCUBE2 0.31 Moderate
ENPP1-SLC16A6 0.33 Moderate
 GFRA1-KCNJ11 0.33 Moderate
GFRA1-SCUBE2 0.37 Moderate
ITPR1-LRIG1 0.38 Moderate
ITPR1-SLC16A6 0.41 Moderate
KCNJ11-LRIG1 0.30 Moderate
KCNJ11-PRRT3 0.46 Moderate
KCNJ11-PTPRT 0.30 Moderate
KCNJ11-SCUBE2 0.43 Moderate
KCNJ11-SUSD3 0.38 Moderate
LRIG1-PTGER3 0.34 Moderate
LRIG1-PTPRT 0.34 Moderate
LRIG1-SCUBE2 0.37 Moderate
LRIG1-SLC16A6 0.35 Moderate
LRIG1-SUSD3 0.43 Moderate
PTGER3-SCUBE2 0.45 Moderate
PTGER3-SUSD3 0.34 Moderate
PTPRT-SCUBE2 0.41 Moderate
SCUBE2-SUSD3 0.38 Moderate
SCUBE2-TSPAN1 0.30 Moderate
CA12-KCNJ11 0.35 Moderate
CA12-SLC16A6 0.47 Moderate
CEACAM6-ITGB6 0.30 Moderate
CEACAM6-TMEM86A 0.35 Moderate
CEACAM6-TSPAN1 0.41 Moderate
HR+/HER2+ ENPP1-SLC16A6 0.31 Moderate
ERBB2-FGFR4 0.41 Moderate
ERBB2-ITGB6 0.44 Moderate
ERBB2-TMEM132A 0.31 Moderate
ERBB2-TMEM86A 0.46 Moderate
FGFR4-TMEM132A 0.52 Good
 FGFR4-TMEM86A 0.42 Moderate
KCNJ11-PRRT3 0.49 Moderate
AKR1A1-ERBB2 0.32 Moderate
AKR1A1-TMEM132A 0.36 Moderate
AKR1A1-TMEM86A 0.47 Moderate
B3GNT3-CEACAM6 0.42 Moderate
B3GNT3-SPNS2 0.58 Good
CEACAM6-ERBB2 0.42 Moderate
CEACAM6-TMEM86A 0.45 Moderate
ERBB2-FGFR4 0.35 Moderate
ERBB2-HRH1 0.38 Moderate
HR-/HER2+
ERBB2-ITGB6 0.41 Moderate
ERBB2-TMEM132A 0.33 Moderate
ERBB2-TMEM86A 0.57 Good
FGFR4-ITGB6 0.43 Moderate
FGFR4-TMEM132A 0.32 Moderate
HRH1-ITGB6 0.49 Moderate
HRH1-TMEM86A 0.47 Moderate
ITGB6-TMEM86A 0.41 Moderate
SLC4A5-TMEM86A 0.31 Moderate
ADCY7-GPR84 0.44 Moderate
B3GNT3-TMEM71 0.36 Moderate
TNBC
GPR84-MUC16 0.38 Moderate
MUC16-TMEM71 0.32 Moderate

Legend and footnotes. HR: hormone receptor; TNBC: triple negative breast cancer; +: positive; -: negative.

Supplementary Table 8. Ongoing/already terminated CAR-T trials involving breast cancer patients

Start Countries Status Phase Cancer Target Title URL

 Treated Blood Cells,
Cyclophosphamide,
United Breast/Colon/Lung/Ovarian/Fallopian/Pancreatic/ Fludarabine Phosphate, https://clinicaltrials.gov/show/
2007 Terminated 1 CEA
Kingdom Stomach/Gastric and Aldesleukin in NCT01212887
Treating Patients With
Cancer
Trial of 2nd Generation
Anti-CEA Designer T https://clinicaltrials.gov/show/
2008 United States Suspended 1 Breast CEA
Cells in Metastatic NCT00673829
Breast Cancer
Her2 and TGFBeta
Breast/Colon/Esophageal/Head and Cytotoxic T Cells in https://clinicaltrials.gov/show/
2009 United States Completed 1 HER2
Neck/Lung/Pancreatic/Prostate/Stomach/Gastric Treatment of Her2 NCT00889954
Positive Malignancy
Treatment of
Chemotherapy
Refractory Human
Unknown Breast/Endometrial/Liver/Ovarian/Fallopian/Stomach/ https://clinicaltrials.gov/show/
2013 China 1-2 HER2 Epidermalgrowth Factor
status Gastric NCT01935843
Receptor-2( HER-2)
Positive Advanced Solid
Tumors
cMet CAR RNA T Cells https://clinicaltrials.gov/show/
2013 United States Completed 1 Breast cMet
Targeting Breast Cancer NCT01837602
A Clinical Research of
https://clinicaltrials.gov/show/
2014 China Recruiting 1 Breast/Colon/Lung/Pancreatic/Stomach/Gastric CEA CAR T Cells Targeting
NCT02349724
CEA Positive Cancer
Phase I/II Study of Anti-
Mucin1 (MUC1) CAR T
Unknown https://clinicaltrials.gov/show/
2015 China 1-2 Breast/Liver/Lung/Pancreatic MUC1 Cells for Patients With
status NCT02587689
MUC1+ Advanced
Refractory Solid Tumor
Treatment of Relapsed
and/or Chemotherapy
Unknown Breast/Endometrial/Mesothelioma/Ovarian/Fallopian/ Mesotheli https://clinicaltrials.gov/show/
2015 China 1 Refractory Advanced
status Pancreatic n NCT02580747
Malignancies by CART-
meso
Chimeric Antigen https://clinicaltrials.gov/show/
2015 China Completed 1-2 Breast HER2
Receptor-Modified T NCT02547961
 Cells for Breast Cancer
Malignant Pleural
Disease Treated With
Autologous T Cells
Mesotheli https://clinicaltrials.gov/show/
2015 United States Recruiting 1 Breast/Lung/Mesothelioma Genetically Engineered
n NCT02414269
to Target the Cancer-
Cell Surface Antigen
Mesothelin
Treatment of Relapsed
and/or Chemotherapy
Unknown Brain/CNS/Breast/Colon/Liver/Lymphoid https://clinicaltrials.gov/show/
2015 China 1 CD133 Refractory Advanced
status Leukemia/Myeloid Leukemia/Ovarian/Fallopian/Pancreatic NCT02541370
Malignancies by
CART133
CAR-T Hepatic Artery
Infusions and Sir- https://clinicaltrials.gov/show/
2015 United States Completed 1 Liver Metastases CEA
Spheres for Liver NCT02416466
Metastases
Genetically Modified T-
Cell Therapy in Treating https://clinicaltrials.gov/show/
2016 United States Recruiting 1 Breast/Lung/Lymphoid Leukemia/Lymphoma ROR1
Patients With Advanced NCT02706392
ROR1+ Malignancies
Autologous T Cells
https://clinicaltrials.gov/show/
2016 United States Recruiting 1 Breast/Melanoma cMet Expressing MET scFv
NCT03060356
CAR (RNA CART-cMET)
A Dose Escalation Phase
Breast/Colon/Myelodysplastic Syndrome/Myeloid I Study to Assess the
Belgium,Unite https://clinicaltrials.gov/show/
2016 Recruiting 1-2 Leukemia/Myeloma/Ovarian/Fallopian/Pancreatic/Urotheli NKG2D Safety and Clinical
d States NCT03018405
al Activity of Multiple
Cancer Indications
Chimeric Switch
Receptor Modified T
Cells for Patients With https://clinicaltrials.gov/show/
2016 China Recruiting 1 Breast/Colon/Lung/Lymphoma/Pancreatic/Renal PD-L1
PD-L1+ Recurrent or NCT02930967
Metastatic Malignant
Tumors
2016 China Recruiting 1 Breast/Nasopharyngeal EPCAM EpCAM CAR-T for https://clinicaltrials.gov/show/
Treatment of NCT02915445
Nasopharyngeal
Carcinoma and Breast
 Cancer
CAR-pNK Cell
Immunotherapy in
Unknown Brain/CNS/Breast/Colon/Liver/Lung/Pancreatic/Stomach/ https://clinicaltrials.gov/show/
2016 China 1-2 MUC1 MUC1 Positive Relapsed
status Gastric NCT02839954
or Refractory Solid
Tumor
A Clinical Research of
Brain/CNS/Breast/Colon/Lung/Ovarian/Fallopian/ https://clinicaltrials.gov/show/
2016 China Recruiting 1-2 HER2 CAR T Cells Targeting
Pancreatic/Stomach/Gastric NCT02713984
HER2 Positive Cancer
Mesotheli T-Cell Therapy for https://clinicaltrials.gov/show/
2016 United States Recruiting 1 Breast
n Advanced Breast Cancer NCT02792114
Administering
Peripheral Blood
Lymphocytes
Transduced With a https://clinicaltrials.gov/show/
2017 United States Recruiting 1-2 Breast/Melanoma/Ovarian/Fallopian/Pancreatic/Renal CD70
CD70-Binding Chimeric NCT02830724
Antigen Receptor to
People With CD70
Expressing Cancers
CAR-T Hepatic Artery
Infusions or Pancreatic
Active, not Venous Infusions for https://clinicaltrials.gov/show/
2017 United States 1 Liver Metastases and Pancreatic cancer CEA
recruiting CEA-Expressing Liver NCT02850536
Metastases or Pancreas
Cancer
CAR-T Intraperitoneal
Infusions for CEA-
Expressing
https://clinicaltrials.gov/show/
2018 United States Recruiting 1 Breast/Colon/Pancreatic/Peritoneal/Stomach/Gastric CEA Adenocarcinoma
NCT03682744
Peritoneal Metastases
or Malignant Ascites
(IPC)
Binary Oncolytic
Adenovirus in
Not Yet Bladder/Breast/Colon/Esophageal/Head and Combination With https://clinicaltrials.gov/show/
2019 USA 1 HER2
Recruiting Neck/Lung/Pancreatic/Salivary Gland/Stomach/Gastric HER2-Specific CAR VST, NCT03740256
Advanced HER2 Positive
Solid Tumors (VISTA)
 Haplo / Allogeneic
NKG2DL- targeting
Colorectal Cancer/Triple Negative Breast
Not yet Chimeric Antigen https://clinicaltrials.gov/show/
2019 Malaysia 1 Cancer/Sarcoma/Nasopharyngeal Carcinoma/Prostate NKG2DL
recruiting Receptor-grafted ## T NCT04107142
Cancer /Gastric Cancer
Cells for Relapsed or
Refractory Solid Tumour
C7R-GD2.CART Cells for
Relapsed Neuroblastoma/Refractory Patients With Relapsed
Neuroblastoma/Relapsed Osteosarcoma/Relapsed Ewing or Refractory https://clinicaltrials.gov/show/
2019 United States Recruiting 1 GD2
Sarcoma/Relapsed Rhabdomyosarcoma/Uveal Neuroblastoma and NCT03635632
Melanoma/Phyllodes Breast Tumor Other GD2 Positive
Cancers (GAIL-N)
A Study of CART-
Non-Small Cell Lung Cancer/ Ovarian Cancer/ Fallopian
TnMUC1 in Patients https://clinicaltrials.gov/show/
2019 United States Recruiting 1 Tube Cancer/ Triple Negative Breast Cancer/ Multiple TnMUC1
With TnMUC1-Positive NCT04025216
Myeloma/ Pancreatic Ductal Adenocarcinoma
Advanced Cancers
Autologous huMNC2-
MUC1* (a CAR44 T Cells for Breast
https://clinicaltrials.gov/show/
2019 United States Recruiting 1 Metastatic Breast Cancer cleaved Cancer Targeting
NCT04020575
form) Cleaved Form of MUC1
(MUC1*)

Supplementary Table 9. Main alternative surface targets for CAR-T and ADC in breast cancer

Position in the SAM list of significantly differentially Position in the SAM list of significantly differentially
Additional surface Reason for not being expressed genes - Intrinsic subtypes expressed genes - Immunohistochemical subtypes
targets included
Luminal A Luminal B HER2-E Basal-like HR+/HER2- HR+/HER2+ HR-/HER2+ TNBC
Position in the SAM list
CEA/CEACAM5 of up/down-regulated 6656 1301 724 11487 4809 528 1298 12073
genes
Position in the SAM list
MUC1 of up/down-regulated 870 9123 5608 12065 2377 647 10106 12671
genes
 Ganglioside codified by
GD2 - - - - - - - -
multiple genes
Position in the SAM list
NKG2D/KLRK1 of up/down-regulated 7985 9545 3074 4659 9452 6841 5308 4646
genes
Position in the SAM list
CD20/MS4A1 of up/down-regulated 8617 10446 2459 3595 10387 8938 4387 3391
genes
41.4% di missing gene
MSLN - - - - - - - -
expression data
Position in the SAM list
EPCAM of up/down-regulated 12891 3592 380 1329 13212 5718 495 1553
genes
Position in the SAM list
PD-L1/CD274 of up/down-regulated 11150 7172 1478 2949 11278 7347 2452 3131
genes
Position in the SAM list
ROR1 of up/down-regulated 7887 12393 8271 1222 10543 10773 5010 2733
genes
Position in the SAM list
of up/down-regulated
cMET - - - - 12757 13750 697 498
genes or not
differentially expressed
Not significantly
differently expressed
CD133/PROM1 - - - - - - - -
among the different
subtypes
Position in the SAM list
TROP-2/TACSTD2 of up/down-regulated 4512 12243 8337 4321 7507 10441 8017 5369
genes
Position in the SAM list
HER3/ERBB3 of up/down-regulated 660 1467 10485 12832 352 1400 12852 13696
genes
65-72% ND-L in normal
LIV-1/SLC39A6 166 110 13119 13038 51 1580 13916 13889
tissues
Legend and captions. HER2-E: HER2-Enriched; HR: hormone receptors; TNBC: triple negative breast cancer; +: positive; -: negative; SAM:
significance analysis of microarray. In the target column, the gene names are reported in italic.

Supplementary Table 10. Concordance of subtype-specificity between the METABRIC database and our study results

METABRIC
SUBTYPE AGREEMENT - 1 COHEN'S KAPPA P AGREEMENT - 2 COHEN'S KAPPA P
Luminal A 79% 0.53 0.002 94% 0.88 <0.001
Luminal B 88% 0.64 <0.001 94% 0.94 <0.001
HER2E 91% 0.74 <0.001 91% 0.74 <0.001
Basal 91% 0.71 <0.001 91% 0.71 <0.001
HR+HER2- 88% 0.75 <0.001 100% 1.00 <0.001
HR+HER2+ 76% 0.39 0.026 97% 0.94 <0.001
HER2+ 94% 0.84 <0.001 94% 0.84 <0.001
TNBC 94% 0.80 <0.001 97% 0.90 <0.001
HOSPITAL CLINIC SERIES
SUBTYPE AGREEMENT - 1 COHEN'S KAPPA P AGREEMENT - 2 COHEN'S KAPPA P
Luminal A 82% 0.61 0.044 91% 0.81 0.007
Luminal B 82% 0.39 0.197 91% 0.74 0.014
HER2E 91% 0.81 0.007 91% 0.81 0.007
Basal 91% -0.05 0.875 91% -0.05 0.875
HR+HER2- 82% 0.63 0.036 91% 0.82 0.007
HR+HER2+ 55% 0.06 0.843 100% 1.00 <0.001
HER2+ 91% 0.81 0.007 100% 1.00 <0.001
TNBC 91% -0.05 0.875 100% 1.00 0.001

Legend and captions. HR: hormone receptors; TNBC: triple negative breast cancer; +: positive; -: negative.

Supplementary Figures
Supplementary Figure 1. Brief overview of ADC (A) and CAR-T (B) therapeutic approaches
Legend. CAR: chimeric antigen receptor; ADC: antibody-drug conjugate; MHC I: type 1 major histocompatibility complex; TAA: tumor associated
antigen; TCR: t cell receptor.

Supplementary Figure 2. Gene expression profiles of intrinsic and immunohistochemical subtypes of breast cancer

Legend and captions. Supervised cluster of the PAM50 intrinsic subtypes (A) and IHC surrogate subtypes (B) of breast cancers. Sample and gene
expression data from tumor samples of the same subtype have been combined into a single category. For each gene in a class, we calculated the
standardized mean difference between the gene’s expression in that class vs. its overall mean expression in the dataset using a 3-class Significance
Analyses of Microarrays. The red color represents relative high gene expression, green represents relative low gene expression, and black represents
median gene expression. HR: hormone receptors; +: positive; -: negative.

Supplementary figure 3. Venn diagram showing the overlap among intrinsic subtypes’ (A) and surrogate subtypes’ (B) 200-top-expressed
gene lists

Legend and captions. HR: hormone receptors; +: positive; TNBC: triple negative breast cancer

Supplementary figure 4. Box plots representing mRNA levels of each target gene according to IHC or molecular subtype in the PAM50
patients cohort
Legend and captions. Gene expression data from 470 patients with breast cancer treated at the Hospital Clinic of Barcelona to whom an
investigational PAM50 test, including 11/36 of our potential targets, had been previously applied. We checked for differences in mRNA relative
transcript abundance among immunohistochemical and molecular subtypes. When mRNA levels for a specific gene resulted to be higher in a
subtype compared to the others, we considered such gene as a confirmed potential target for that subtype. When no differences in mRNA levels
according to subtype were observed, its product was not considered a subtype-specific target. HR: hormone receptors; +: positive; -: negative;
TNBC: triple negative breast cancer; Basal: Basal-like, Her2: HER2-Enriched; LumA: Luminal A; LumB: Luminal B.
Supplementary figure 5. Differential expression of potential target genes in breast cancer cell
lines (A) and mRNA levels for each gene according to cell line (B)

Legend and captions. Supervised cluster of the different breast cancer cell lines. Each class
represents a cell line sample with respective gene expression data, compared to the others. For each
gene in a class, we calculated the standardized mean difference between the gene’s expression in
that class vs. its overall mean expression in the dataset using a multiclass Significance Analyses of
Microarrays. The analysis was restricted to potential target genes available in the Breast 360 TM
Codeset. The red color represents relative high gene expression, green represents relative low gene
expression, and black represents median gene expression. TNBC: triple negative breast cancer; HR:
hormone receptors; +: positive; -: negative.