310
Steroid Receptors in Hereditary Breast Carcinomas
Associated with BRCA1 or BRCA2 Mutations or
Unknown Susceptibility Genes
Niklas Loman, M.D.
Oskar Johannsson, M.D., Ph.D.
Pär-Ola Bendahl, Ph.D.
Åke Borg, Ph.D.
Mårten Fernö, Ph.D.
Håkan Olsson, M.D., Ph.D.
Jubileum Institute, Department of Oncology, Uni-
versity Hospital, Lund, Sweden.
The current study was supported by grants from
the Swedish Cancer Society, the Nordic Cancer
Union, the Mrs. Berta Kamprads Foundation, the
University of Lund Medical Faculty, the CTRF, the
Gunnar Arvid and Elisabeth Nilsson Foundation, the
John and Augusta Persson Foundation, the Hospi-
tal of Lund Foundations, and King Gustav V’s
Jubilee Foundation.
Address for reprints: Niklas Loman, M.D., Jubileum
Institute, Department of Oncology, University Hos-
pital, S-221 85 Lund, Sweden.
Received September 24, 1997; revision received
January 16, 1998; accepted January 16, 1998.
© 1998 American Cancer Society
BACKGROUND. The expression of steroid receptors is a common feature of both
male and female breast carcinomas and is also one of the most important prog-
nostic factors for patients with this disease. Steroid receptor levels in BRCA1-
related breast carcinoma have reportedly been low. Little data on steroid receptor
levels have been reported with regard to BRCA2.
METHODS. Steroid receptor levels were analyzed in 27 breast carcinomas associated
with BRCA1 mutations, 14 associated with BRCA2 mutations, and 32 from indi-
viduals who had hereditary breast carcinoma but no detectable mutations of either
BRCA1 or BRCA2. Breast carcinomas from 32 consecutive male patients, 6 of whom
had mutations of BRCA2, were also examined for steroid receptors. Estrogen
receptor (ER) and progesterone receptor (PgR) analyses were performed with
radioligand or enzyme immunoassay techniques on tumor cytosol preparations.
Germline mutation screening and detection were performed using the protein
truncation test, single strand conformation polymorphism, and direct sequencing
on DNA from normal tissue.
RESULTS. The BRCA1-related tumors expressed significantly lower levels of ER than
tumors from the other hereditary groups. The PgR levels were significantly lower in
the BRCA1-related cases than in the hereditary cases not related to BRCA1 or
BRCA2, but not significantly lower than in the BRCA2-related cases. Fourteen of 32
(44%) of the hereditary tumors not related to BRCA1 or BRCA2 had PgR levels
exceeding 100 fmol/mg of protein. The tumors from male patients with BRCA2-
related disease did not have receptor levels that differed from those in non-BRCA2-
related tumors.
CONCLUSIONS. BRCA1- and BRCA2-related breast tumors were distinct in their
expression of steroid receptors. Moreover, a subgroup of tumors not related to
BRCA1 or BRCA2 manifested a strongly positive PgR phenotype rarely seen in
BRCA1- and BRCA2-related tumors. These characteristics may be of relevance to
the treatment and follow-up of high risk individuals in these families and may help
identify a homogenous category of hereditary breast carcinomas not related to
BRCA1 or BRCA2 in which new susceptibility genes may be sought. Cancer 1998;
83:310 –9. © 1998 American Cancer Society.
KEYWORDS: hereditary breast carcinoma, male breast carcinoma, estrogen recep-
tor, progesterone receptor, BRCA1, BRCA2.
S usceptibility to breast carcinoma is inherited by transmission of
an autosomal dominant allele in approximately 5–10% of all cas-
es.1,2 Two major tumor suppressor genes associated with hereditary
breast carcinoma have been identified, BRCA1 and BRCA2.3–5 Germ-
line mutations in BRCA1 are associated with an increased risk of
breast and ovarian carcinoma in females; the risk of developing an
 Steroid Receptors in Hereditary Breast Carcinoma/Loman et al.
invasive breast carcinoma is estimated at approxi-
mately 70% by age 70 years.6 Germline mutations in
BRCA2 confer an increased risk for both female and
male breast carcinoma. Other malignancies, such as
cancer of the prostate, pancreas, larynx, ovarium, cer-
vix, and ureter, as well as malignant melanoma of the
eye, may also be seen more frequently than expected
in BRCA2 mutation carriers.6 –9 The risk of developing
breast carcinoma was 82% by age 80 years in one
study of a large BRCA2 kindred10 and almost 100%
among Icelandic breast carcinoma families with the
BRCA2 founder mutation.11 However, risk estimates
have been lower in population-based studies. In a
study of Ashkenazi Jews carrying any of three recur-
rent BRCA1 and BRCA2 mutations, the risk for breast
carcinoma was 56% at age 70 years.12
Depending on the population studied, germline
mutation in BRCA1 can be detected in 9 –79% of fam-
ilies with 3 or more cases of breast and/or ovarian
carcinoma, whereas BRCA2 accounts for an additional
8 – 64% of remaining families.13 Minor fractions of the
total number of inherited breast carcinomas are asso-
ciated with rare cancer syndromes of identified or
mapped genetic origin, including the Li–Fraumeni
syndrome and TP53,14 the Cowden disease and PTEN/
MMAC1,15,16 and the Peutz–Jegher syndrome gene on
chromosome 19p.17 However, a considerable percent-
age of hereditary breast carcinomas remain unrelated
to a definite gene. In our previous study of 106 Scan-
dinavian breast carcinoma families, the frequencies of
BRCA1 and BRCA2 mutations were 23% and 11%, re-
spectively, rendering almost two-thirds of families ge-
netically uncharacterized.18 The search for new breast
carcinoma susceptibility genes is currently intense; it
involves various procedures such as linkage analysis
and/or mapping of chromosomal deletions in tumors.
These approaches are likely to be successful if occur-
rences in the remaining families are due to one or a
few additional major tumor suppressor genes, but
they are less useful in a more heterogeneous situation.
Alternatively, new insights into the causes of heredi-
tary breast carcinoma may be obtained from func-
tional studies of the known BRCA proteins and their
interacting cellular components, as well as from phe-
notypic studies of genetically modified animals or of
tumors in families with genetic predisposition.
Recent evidence suggests that the BRCA1 and
BRCA2 proteins are involved in maintaining genome
integrity, possibly by participating with the Rad51
protein in recombination linked repair of double-
stranded DNA breaks and by transcriptional coactiva-
tion in complex with RNA polymerase II holoen-
zyme.19 –21 Both genes demonstrate a virtually
indistinguishable spatial and temporal pattern of ex-
311
pression in many fetal and adult tissues, which is most
prominent in proliferating compartments undergoing
differentiation.22 In the breast, BRCA1 and BRCA2
mRNA expression are induced during puberty and
pregnancy, suggesting a regulation by sex hormones.22
Tumors from BRCA1 and BRCA2 mutation carriers are
characterized by a significantly higher number of
chromosomal aberrations than are found in sporadic
breast carcinoma, which indicates that both genes are
a critical factor in DNA repair. These aberrations also
show gene specific alteration patterns, suggesting that
the accumulation of somatic changes in tumor pro-
gression may follow unique pathways that are related
to genetic origin.23
Clinical and histopathologic analysis of BRCA1-
and BRCA2-related tumors further emphasizes the
distinction between sporadic and differing types of
hereditary breast carcinoma. BRCA1-related breast
carcinoma was found to be poorly differentiated duc-
tal carcinoma, often with dense lymphocyte infiltra-
tion, DNA aneuploidy, and a high S-phase fraction.24
Similar results were obtained in a subsequent study, in
which BRCA1 tumors were more often found to be a
medullary or atypical medullary type, more pleomor-
phic, with less tubule formation and a higher mitotic
count than sporadic tumors, whereas BRCA2 tumors
had less tubule formation than sporadic cases but
otherwise fewer specific features.25
Steroids, and especially estrogen, are central reg-
ulators of the growth and differentiation of the normal
mammary gland and are also thought to be involved
in the development and progression of breast carci-
noma. Estrogen receptor (ER) and progesterone re-
ceptor (PgR) status are among the most important and
most commonly evaluated prognostic factors in breast
carcinoma as well as the most important predictors of
response to endocrine therapy.26 Female breast carci-
noma is ER and PgR positive in about 65% and 50% of
all cases, respectively, and ER status especially shows
an age-dependent variation in which tumors from
younger patients are less often positive.27 Male breast
carcinoma most often has an ER positive phenotype.28
We have previously reported a low frequency of ER
and PgR positive immunostaining in BRCA1-related
breast carcinoma.24 Data on BRCA2 and receptor sta-
tus is scarce; Karp et al. reported on four patients of
Ashkenazi descent who were all ER positive.29
In the current study, we have used biochemical
techniques for quantitative measurement of ER and
PgR in three groups of hereditary breast carcinoma,
consisting of tumors from female BRCA1 and BRCA2
mutation carriers as well as tumors from female pa-
tients with a defined heredity for breast and/or ovar-
ian carcinoma but without signs of mutation in BRCA1
312 CANCER July 15, 1998 / Volume 83 / Number 2
or BRCA2. These groups are compared with one an-
other and, in analyses stratified for age and calendar
time, also compared with 8948 consecutive tumors
from breast carcinoma patients treated in the South
Sweden Health Care Region during the period 1978 –
1996. In addition, receptor levels in six breast tumors
from male BRCA2 mutation carriers are compared
with a group of 26 sporadic breast tumors from males.
We confirm our previous finding of significantly lower
ER and PgR values in BRCA1-related tumors and re-
port on the identification of non-BRCA1/BRCA2-re-
lated hereditary cases with high ER and PgR levels. The
results may have implications for defining a new sub-
class of hormone-sensitive hereditary breast carci-
noma as well as for the clinical management of these
patients.
MATERIALS AND METHODS
Patients
The three groups of hereditary breast carcinoma diag-
nosed during the period 1978 –1996 were collected
from a set of Scandinavian kindreds with familial
breast or breast-ovarian carcinoma analyzed for germ-
line mutation in BRCA1 and BRCA2.18 The first group
(BRCA1-related) included 25 tumors from 20 patients
in 15 families with 8 different proven BRCA1 germline
mutations. An additional two cases from a kindred
(Lund1) with a strong linkage to BRCA1 (LOD score
1.6), as well as LOH of the wild-type BRCA1 allele in
five of six analyzed tumors from haplotype carriers,
were included. The second group (BRCA2-related) in-
cluded 14 tumors from 13 patients in 8 families with 7
different BRCA2 germline mutations. A third group
(non-BRCA1/BRCA2) was composed of 30 families in
which screening for BRCA1 and BRCA2 had been neg-
ative. These were families with at least 3 first-degree
relatives affected by breast and/or ovarian carcinoma,
1 of whom was diagnosed before age 50 years. Alter-
natively, these families had 2 affected first-degree rel-
atives, 1 of whom was diagnosed before age 40 years,
or 1 single affected woman younger than 30 years.
This pattern could be compatible with a dominant
mendelian heritage. One breast carcinoma patient
from each of the 30 non-BRCA1/BRCA2 families was
included in this study. In two cases, bilateral breast
carcinomas were included; thus, a total of 32 fresh
frozen tumors were analyzed.
Informed consent was obtained before mutation
analysis was performed, and the families were fol-
lowed up through the oncogenetic reception jointly
run by the Departments of Oncology and Clinical Ge-
netics in Lund.
Since 1978, fresh tumor material for hormone re-
ceptor analysis and flow cytometry has been sent to
our laboratory for routine analysis after breast carci-
noma surgery at the different hospitals in the South
Sweden Health Care Region. Thus, a bank of almost
9000 breast carcinoma tumors have been collected
and tissues analyzed in these respects. The groups of
hereditary breast carcinoma tissues were compared
with one another and with this consecutive reference
material, which mainly consisted of sporadic breast
carcinoma. For the comparisons, this material was
stratified according to patient age and calendar year of
diagnosis.
Thirty-two breast carcinoma tumors from male
patients from 1985–1996 were sent to our laboratory
for receptor analysis. These consecutive cases were
also included separately in the study.
Methods
Germline mutations in BRCA1 and BRCA2 were de-
tected by screening the DNA extracted from periph-
eral lymphocytes collected from affected individuals.
In 31 of the 32 men included in the study, mutations
were identified in DNA obtained from fresh frozen
tumor material. In these cases, mutations were con-
firmed in the germline by verification in archived par-
affin blocks of normal tissue. The methods used were
the protein truncation test (PTT), single-strand con-
formation polymorphism (SSCP), and direct sequenc-
ing. We estimated the sensitivity for detection of mu-
tation to be approximately 80%.18
Estrogen receptor (ER) levels were analyzed ac-
cording to clinical praxis with isoelectric focusing in
polyacrylamide gel (IF) or enzyme immunoassay (EIA;
Abbot Laboratories).30 Similarly, progesterone recep-
tor (PgR) levels were analyzed using the multiple-
point dextran-coated charcoal technique (DDC), or
EIA.31,32 The interassay agreements were found to be
highly concordant, although higher levels were ob-
tained with the EIAs. Thus, all values with IF and DDC
were recalculated to allow for comparison of data
from different time periods.27,33,34 The cutoff level for
a receptor positive tumor was set at 25 fmol/mg pro-
tein in our laboratory.
In some cases, when women have had two tumors
that have clinically been considered separate, both
were included separately in this study. Clinical data on
tumor stage was collected from case records.
Statistics
Age differences between the groups were evaluated
using a two-tailed Student’s t test, whereas receptor
levels, due to considerable skewness, were compared
using the nonparametric Kruskal–Wallis test. Due to
low cell frequencies, Fisher’s exact test was used for
evaluation of stage differences among groups. Differ-

TABLE 1
Clinical Stages of Disease in Three Groups of Hereditary Breast
Carcinomas
No. of cases
Stage BRCA1 BRCA2 non-B1/B2
I 12 2 11
II 14 9 16
III 0 2 2 4
IV 0 0 1 1
Unknown 1 1 2 4
Total 27 14 32
ences in distribution of receptor positive and negative
tumors were analyzed using chi-square tests.
Receptor levels in breast carcinoma are age-de-
pendent. To rule out the possibility that observed sig-
nificant differences in hormone receptor levels were a
consequence of differences in age distribution, the
groups with hereditary breast carcinoma were com-
pared with reference material, which consisted of 8948
consecutive, mainly sporadic breast carcinomas. We
stratified the reference material into 5-year intervals
according to both age and calendar time at diagnosis,
transformed the values toward normality (the square
root), and computed the mean and standard deviation
in each stratum. For each of the three hereditary
groups, we then computed a series of differences be-
tween observed transformed receptor level and the
corresponding mean. The approximate normal distri-
bution of the sum of those differences led to an age-
and calendar time– corrected test of the no-difference
hypothesis.
All statistical tests performed were two-tailed; and
when significance is mentioned without reference to a
level, the level of P , 0.05 is assumed. Statistical
calculations were made using Stata 5.0 software.35
RESULTS
Breast Carcinomas from Females
Age distribution was similar in the three groups of
hereditary breast carcinoma: BRCA1 median 5 44.0
years, range 5 26 – 60 (n 5 27); BRCA2 median 5 45.0,
range 5 27– 82 (n 5 14); non-BRCA1/BRCA2 median 5
47.5, range 5 28 – 81 (n 5 32). Tumor stages (I–IV)
were also similar in the three groups (P 5 0.19) (Table
1). In the cases in which stage was unknown, this was
due to either lack of information (in one case) or
because axillary dissection was not performed (in
three cases).
Screening for statistical differences in ER and PgR
levels among the three groups, using the Kruskal–
Steroid Receptors in Hereditary Breast Carcinoma/Loman et al. 313
Total
25
39
73
FIGURE 1. This dotplot shows estrogen receptor (ER) levels in the different
groups of patients with hereditary breast carcinoma. Median values and the
threshold for receptor positivity (25 fmol/mg protein) are marked in the plot.
Log scale on y-axis.
Wallis test, revealed differences in both receptor types.
P 5 0.0006 (ER) and P 5 0.0014 (PgR), respectively.
Pairwise comparisons of ER levels (fmol/mg pro-
tein) between the groups revealed significantly lower
values among BRCA1 tumors (median 5.4, range
0 –270) compared with BRCA2 tumors (median 48.5,
range 0 –550) (P 5 0.014) and non-BRCA1/BRCA2 tu-
mors (median 44.5, range 0 – 410) (P 5 0.0002). No
statistical difference was observed between BRCA2 tu-
mors and non-BRCA1/BRCA2 tumors (Fig. 1).
BRCA1 tumors were found to manifest signifi-
cantly lower PgR levels (fmol/mg protein) (median 1.1,
range 0 –196) compared with non-BRCA1/BRCA2 tu-
mors (median 62.0, range 0 –1960) (P 5 0.0004). A
nonsignificant trend toward lower PgR values com-
pared with BRCA2 tumors was observed (median 5
19.0, range 5 0 – 600) (P 5 0.075). The difference in
PgR levels between BRCA2 tumors and non-BRCA1/
BRCA2 tumors was not statistically significant (P 5
0.13). However, whereas only 1 of 26 BRCA1 tumors
(3.8%) and 1 of 13 BRCA2 tumors (7.7%) manifested
high PgR values (.100 fmol/mg protein), this was
evident in 14 of 32 (44%) of the non-BRCA1/BRCA2
tumors (Fig. 2).
Similar results were obtained when the frequency
of ER positivity (ER1) and PgR positivity (PgR1) was
compared among the three groups of hereditary
breast carcinoma. Receptor positivity was defined as a
receptor value $ 25 fmol/mg protein. BRCA1 tumors
were significantly less ER1 (15%) compared with
BRCA2 tumors (57%) (P 5 0.005) and non-BRCA1/
BRCA2 tumors (59%) (P , 0.001). BRCA1 tumors were
also significantly less PgR1 (19%) than non-BRCA1/
314 CANCER July 15, 1998 / Volume 83 / Number 2
FIGURE 2. This dotplot shows progesterone receptor (PgR) levels in the
different groups of patients with hereditary breast carcinoma. Median values
and the threshold for PgR positivity (25 fmol/mg protein) are marked in the plot.
Log scale on y-axis.
TABLE 2
Estrogen Receptor (ER) and Progesterone Receptor (PgR) Status in
Tumors from Three Groups of Hereditary Breast Carcinoma
No. (%) of cases
ER1
BRCA1 4/27 (15%)
BRCA2 8/14 (57%)
non-BRCA1/BRCA2 19/32 (59%)
BRCA2 tumors (59%) but not significantly different
from BRCA2 tumors (31%) (P 5 0.42). Again, there was
a trend toward a significant difference between PgR
status in BRCA2 and non-BRCA1/BRCA2 cases (P 5
0.082). There was no such trend in ER status (Table 2).
To compare receptor levels between different
groups of hereditary and sporadic breast carcinoma
and to preclude the impact of age on receptor values,
an age- and calendar year–stratified analysis was per-
formed, comparing the three hereditary groups with a
reference group of 8948 consecutive breast tumors
collected and analyzed between the years 1978 and
1996. BRCA1 tumors had significantly lower ER levels
(P 5 0.0008) and PgR levels (P 5 0.0004) than the
reference group, which mainly consisted of sporadic
cases. Receptor levels in the BRCA2 and non-BRCA1/
BRCA2 tumors did not differ significantly from the
reference group (Figs. 3 and 4).
Regarding the intragenomic localization of the
different mutations within the two genes and its effect
on ER and PgR status, no clear trend was observed.
The receptor negative and positive cases appeared
evenly distributed with respect to both genes. Four
bilateral cases were included in the material. Of the
three cases with BRCA1 mutation, one had synchro-
nous tumors with an ER2/PgR1 and an ER2/PgR2
phenotype, another had two synchronous ER2/PgR2
tumors, and a third presented with an ER2/PgR2 and
an ER2/PgR1 tumor at ages 32 and 37 years, respec-
tively. The single case with BRCA2 mutation and bi-
lateral disease had an ER2/PgR2 and an ER2/PgR1
tumor at ages 72 and 75 years, respectively.
Breast Carcinomas from Males
Comparing the ages of breast carcinoma onset be-
tween a group of 6 males with BRCA2 mutation and a
group of 26 males without detectable BRCA2 mutation
revealed a weak trend (P 5 0.15) toward younger age
in the former group (median 64.1 years, range 46 –78,
vs. median 72.6, range 55–93) (Fig. 5). No obvious
differences were observed between the groups regard-
ing the ER and PgR levels. BRCA2 tumors expressed ER
at a median level (fmol/mg protein) of 185, range
1.9 –250; PgR median 90, range 34 –260. This should be
compared with the cases not related to BRCA2: ER
median 245, range 0 –550; PgR median 145, range
0 – 810 (Figs. 6 and 7).
PgR1 DISCUSSION
It has previously been reported that breast tumors
5/26 (19%)
4/13 (31%)
from BRCA1 mutation carriers differ from other breast
19/32 (59%) tumors by having higher histologic grade, DNA aneu-
ploidy, and S-phase values.24,25,36 We have previously
also observed a significantly lower frequency of ER1
and PgR1 in BRCA1 tumors as compared with age-
and stage-matched controls in immunohistochemical
staining of paraffin sections.24 In the current study, in
which largely different and more extensive tumor ma-
terial was studied using biochemical techniques for
receptor analysis, we confirmed and extended our
previous findings, reported by Johannsson et al., by
demonstrating significantly lower ER and PgR levels in
BRCA1 tumors as compared with sporadic tumors and
other tumors from genetically predisposed individu-
als. Hereditary breast carcinoma was categorized here
into three distinct groups. Two were homogeneous
groups associated with identified germline mutations
in the BRCA1 or BRCA2 gene, respectively, and a third,
supposedly heterogeneous, group comprised tumors
from families interpreted as carrying a dominant dis-
ease allele but in whom no mutations in BRCA1 and
BRCA2 had been found. Half of the BRCA1 tumors
showed a complete loss of PgR expression, as com-
pared with 2 of 13 BRCA2 tumors and 6 of 32 non-
BRCA1/BRCA2 tumors. In contrast, close to half of the
non-BRCA1/BRCA2 hereditary tumors manifested
 Steroid Receptors in Hereditary Breast Carcinoma/Loman et al.
FIGURE 3. Estrogen receptor (ER) levels are compared among different groups
of hereditary breast carcinoma—(A) BRCA1, (B) BRCA2, and (C) non-BRCA1/
BRCA2—and the reference material consisting of 8948 consecutive tumors ana-
lyzed since 1978. Dots represent hereditary breast carcinoma cases; boxes rep-
resent reference material and show median and interquartile range. Log scale on
y-axis.
high PgR levels (.100 fmol/mg protein), a phenotype
rarely seen in BRCA1 and BRCA2 tumors.
No significant differences in steroid receptor lev-
els were observed between hereditary tumors related
to BRCA2 or without detectable mutation in the age-
matched comparisons with the reference material
consisting of consecutive, mainly sporadic tumors. In
this analysis, differences between hereditary and non-
hereditary tumors may have been underestimated be-
cause the rate of hereditary tumors in the reference
material could have been expected to be higher for the
younger age groups. Similar results were reported by
Karp et al., who analyzed ER levels in breast carcino-
mas from patients of Ashkenazi descent, a population
with a high frequency of specific founder mutations in
BRCA1 (185delAG and 5382insC) and BRCA2
(6174delT). In their study, breast carcinoma patients
were screened for these mutations and the rates of
ER1 were studied. Tumors from patients with germ-
line mutations in BRCA1 were significantly less often
ER1 than tumors from patients without one of these
two founder mutations. Four cases of breast carci-
noma related to germline mutation in BRCA2 were
also reported; they were all ER1.29
Estrogens are potent mitogens and act via binding
315
to nuclear receptors, ligand-inducible enhancers that
modulate the expression of certain genes by binding
to short DNA sequences, or estrogen responsive ele-
ments (EREs) located in the vicinity of the regulated
genes.37 The PgR gene is a major estrogen-regulated
gene, and high tumor levels of PgR protein are indic-
ative of a functional ER mechanism and hormone-
responsive phenotype. This information is clinically
important and useful in predicting response to endo-
crine therapy. Patients with advanced disease and an
ER2/PgR2 primary tumor seldom respond to tamox-
ifen therapy (the response rate is ,10%), whereas the
response rate among ER1/PgR1 cases is 60 –70%.38
The presence of ER and PgR is also associated with a
more well-differentiated tumor type and is thus a
marker of good prognosis. BRCA1 tumors are, as
shown here, mainly receptor negative and have many
other histopathologically aggressive features, such as
nuclear pleomorphism, high mitotic count, and a pau-
city of tubular formations. However, this is contradic-
tory to reported survival analyses claiming that
BRCA1-related breast carcinoma is associated with a
better prognosis than other hereditary cases or spo-
radic breast carcinoma.36,39,40 A similar paradox is ev-
ident in hereditary nonpolyposis colon carcinoma,
316 CANCER July 15, 1998 / Volume 83 / Number 2

FIGURE 4. Progesterone receptor (PgR) levels are compared among different

groups of hereditary breast carcinoma—(A) BRCA1, (B) BRCA2, and (C) non-
BRCA1/BRCA2—and the reference material consisting of 8948 consecutive tumors
analyzed since 1978. Dots represent hereditary breast cancer cases; boxes rep-
resent reference material and show median and interquartile range. Log scale on
y-axis.

which is associated with a genomic instability and
mutator phenotype but is nonetheless associated with
a better prognosis than sporadic colon carcinoma.41
However, our own experience from studies of BRCA1-
related breast carcinoma patients suggests a survival
rate among BRCA1 cases that is equal to or even worse
than the rate among age- and stage-matched control
patients.42
Structural and functional studies of the BRCA1
and BRCA2 proteins have suggested several shared
features; both have similar cell cycle–specific expres-
sion and subcellular localization, manifest an interac-
tion with the Rad51 protein, and possess transcrip-
tional activities.19,21,43,44,45 Moreover, transcription of
both BRCA1 and BRCA2 is thought to be directly or
indirectly initiated by estrogen stimulation in cell cul-
ture models.46 – 48 In spite of these similarities, there
are indications that different pathogenetic pathways
are involved in BRCA1- and BRCA2-related tumors.
However, recent studies suggest that BRCA1 and
BRCA2 are differentially regulated by sex hormones.
The ratio of BRCA1 to BRCA2 expression is higher in
the female breast than in the male breast, and treat-
ment of mice having undergone ovariectomy with
17b-estradiol or progesterone has given rise to a more
pronounced induction of BRCA1 than of BRCA2.22
This may reflect the gender-specific difference in
BRCA1- and BRCA2-related tumors. Furthermore,
comparative genomic hybridization (CGH) analysis
has shown that BRCA1 and, less often, BRCA2 tumors
have specific patterns of chromosomal aberrations
that are distinct from each other and from sporadic
breast carcinoma.23 This suggests that some initial
genetic events in tumorigenesis may determine a pre-
ferred course and combination of somatic genetic
changes in tumor progression and that these changes
are different in cases related to BRCA1 and BRCA2.
It has been suggested that the hormonal and pro-
liferative properties of breast carcinoma are related to
the situation in the premalignant tissue at the time of
tumor induction.49 In mice, BRCA1 is expressed in
breast tissue during adolescence and pregnancy,
when the levels of ER are also increasing. The induc-
tion of BRCA1-related tumors may occur during a
period of the life cycle when ER levels are low. By the
same token, the expression of BRCA2 may be essential
for mammary gland development during a stage when
ER and PgR levels have increased, leaving a hormone-
 Steroid Receptors in Hereditary Breast Carcinoma/Loman et al.
FIGURE 5. This dotplot shows the age distributions for male breast carci-
noma patients related and not related to BRCA2. Median values are marked in
the plot. The difference is not significant (N.S.). Log scale on y-axis.
FIGURE 6. This dotplot shows ER levels in males with breast carcinomas
related and not related to BRCA2. Median values are marked in the plot. The
difference is not significant. Log scale on y-axis.
dependent imprint on BRCA2-related breast tumors.
Tumors arising in female and male individuals with
dysfunctional BRCA2 do not differ from sporadic
breast carcinoma in steroid receptor content, and they
have in many cases preserved a hormone-sensitive
phenotype. BRCA1 tumors may constitute a hormone-
independent and rapidly proliferating type of breast
carcinoma with an inherent genome instability that
could make them susceptible to certain DNA damag-
ing drugs and other cellular stresses. Obviously,
BRCA1-related, BRCA2-related, and other hereditary
types of breast carcinoma are different pathogenic
and clinical entities that probably require distinct
treatment and follow-up programs and possibly dif-
ferent prophylactic measures. The high receptor levels
317
FIGURE 7. Progesterone (PgR) levels are shown for male breast carcinoma
tumors related to and not related to BRCA2. Median values are marked in the
plot. The difference is not significant. Log scale on y-axis.
and hormone-responsive phenotype seen in some he-
reditary non-BRCA1/BRCA2-related tumors may also
indicate a distinct genetic origin and subgroup of he-
reditary breast carcinoma. Data presented here could
suggest a rationale for trying antiestrogens as chemo-
prevention in the treatment of high risk individuals in
such families. This may also be considered for healthy
women carrying BRCA2 mutations.
In most populations throughout the world, a sig-
nificant proportion of families who have a high risk for
developing breast carcinoma remain genetically un-
characterized.13 Thus, it is of considerable interest
that, in tumors of which an unknown genetic factor
might be the underlying cause, steroid receptor levels
are higher than in tumors associated with BRCA1 and
BRCA2 mutations. The results of the current study
suggest that familial tumors with high levels of PgR
might compose a distinct subgroup of hereditary
breast carcinomas.
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