Funding for Research Areas. https://malebreastcancerblog. 4. Orenstein P. Our feel-good war on breast cancer.
New York
org/2013/05/08/a-200m-advocacy-bump-in-nci-breast-cancer-
research-funding/; http://www.cancer.gov/about-nci/budget/
fact-book/data/research-funding. Accessed January 11, 2016.
Targeting the Cell Cycle in Breast Cancer
Jason P.W. Carey, PhD, and Khandan Keyomarsi, PhD
Over the past several decades, studies have shown that tumor
suppressors and oncogenes play a hierarchal role in influenc-
ing the dynamics of cell cycle regulation in cancer cells, ulti-
mately inducing a degree of deregulation that signals
increased proliferation.1 Cell cycle deregulation lies at the
axis of several hallmarks of cancer, including genomic insta-
bility, cell death, replicative immortality, and sustained pro-
liferative signaling.2 The overarching importance of cell
cycle deregulation as an integral aspect of tumorigenesis is
reflected in the myriad of oncogenes and mutations that
induce deregulation of the cell cycle.3,4 Additionally, the effi-
cacy of therapeutic treatment options today are assessed by
their ability to assert cell cycle control in deregulated
tumor cells, underscoring the importance of understanding
the role of the cell cycle in response to new treatment
strategies.5,6
Breast cancer has a long-established close association
with deregulation of the cell cycle as a mediator of tumor
progression and response to therapy. Over 70% of breast can-
cers are hormone receptor positive, expressing estrogen
receptor (ER), progesterone receptor, or human epidermal
growth factor receptor 2 (HER2).7,8 In this patient cohort,
hormone deprivation therapy (HDT) elicits control over the
cell cycle via the G1-S checkpoint. Loss of G1-S checkpoint
control signifies a persistent resistance mechanism in
response to HDT.9,10 Hormone-negative triple-negative
breast cancers (TNBCs) typically acquire several molecular
alterations that signify deregulation of the cell cycle, includ-
ing frequent p53 mutations, which result in deregulation of
the cell cycle via the loss of p21 control over G1-S transition.
The high level of genomic instability in TNBC tumors is typ-
ically correlated with upregulation or amplification of cyclin
E, a cell cycle protein that develops oncogenic isoforms,
which have been shown to mediate resistance to chemother-
apy and HDT.11-13
Over the past several decades, directly targeting the cell
cycle in breast cancer has been a clinical imperative with lit-
tle success.14 The development of several generations of
256 Breast Diseases: A Year BookÒ Quarterly
Vol 27 No 4 2017
Times. 2013, http://www.nytimes.com/2013/04/28/magazine/
our-feel-good-war-on-breast-cancer.html?_r¼0. Accessed
January 11, 2016.
CDK inhibitors has failed to advance beyond the clinical
trial stage until recently, with the CDK4/6 inhibitor palboci-
clib gaining U.S. Food and Drug Administration (FDA)
approval via improved relapse free-survival in hormone
receptor-positive patients.15-17 As a result, several CDK4/6
inhibitors are currently undergoing clinical trials within the
ER-positive breast cancer patient population.16 Ongoing
research suggests that targeting the cell cycle directly still
remains an effective therapeutic strategy in vitro and in
mouse models, with several clinical compounds under inves-
tigation that target various aspects of the cell cycle pathway
in breast cancer.
CDK4/6 INHIBITORS
Palbociclib has recently gained FDA approval in ER-positive
breast cancer, in combination with HDT (fulvestrant/letro-
zole), and is seeking FDA approval for use in HER2-
positive breast cancer.18,19 Palbociclib has been shown to
improve progression free-survival in hormone receptor-
positive breast cancer patients; however, the effect on overall
survival has been minimal.17 Other CDK4/6 inhibitors, abe-
maciclib and ribociclib, are also currently undergoing clinical
evaluation in ER-positive breast cancer.16 Preclinical models
have predicted several resistance mechanisms to CDK4/6
inhibition that indicate further deregulation of the cell
cycle; this marks a shift away from CDK4/6 cell cycle con-
trol via upregulation of analogous cyclins and CDKs, thus
overcoming CDK4/6 inhibition.20,21 Deregulation of the
G1-S checkpoint in CDK4/6-resistant cells is dictated by
either overexpression of cyclin E or loss of RB expression,
suggesting that the fundamental resistance mechanism
involves alternate activation of the G1-S checkpoint transi-
tion, further strengthening the clinical need for novel cell
cycle inhibitors that target alternate phases of the cell cycle
in response to CDK4/6 resistance mechanisms.
CDK2 AND CYCLIN E
Cyclin E is overexpressed across several breast cancer
subtypes and has an integral role in influencing tumorigene-
sis. In ER-positive breast cancer, cyclin E has been shown to
predict resistance to HDT, both in vitro and in vivo. In TNBC,
more than 50% of tumors harbor overexpression or