Estrogen receptor (ER) breast cancers constitute nearly 75% of all cases and half of all deaths from the disease each year. These tumors are termed luminal and are remarkably heterogeneous in their expression of ER. Tumors that contain only a small percent of ER immunoreactive cells are candidates for treatment with endocrine therapies. However, nearly 40% of luminal tumors will become endocrine resistant and relapse, which persistently occurs over a 5-10 year period. The role of various ER?subpopulations within ER+ tumors is largely unknown. In our previous work, we identified that half of luminal tumors contain an ER? and progesterone receptor (PR)? subpopulation marked by cytokeratin 5 (CK5), a normal breast stem cell marker, and indicator of poor prognosis in breast cancer. CK5+ER?PR? cells display cancer stem cell (CSC) properties such as resistance to endocrine and chemotherapy, and enhanced mammosphere and tumor initiation capacity. We originally described that the natural hormone progesterone and progestins, synthetic analogs used for menopausal hormone therapies, expand the CK5+ breast cancer cell population. We have confirmed this using our original collection of luminal ER+PR+ breast cancer patient-derived xenografts (PDX). Furthermore, we have defined that retinoic acid can block or reverse progestin-induced CK5+ cells. The goal of this proposal is to further investigate the hormone and nuclear receptor mediated mechanisms by which CK5+ER?PR? breast cancer cells are regulated, and how they contribute to disease progression. The hypothesis to be tested is that progestins through PR directly regulate the CK5 gene to produce CK5+ER?PR? CSCs that promote endocrine resistance and tumor recurrence. Our approach will utilize luminal breast cancer cell lines with traceable CK5 expression, our luminal breast cancer PDX that retain the natural mixture of CK5?ER+PR+ and CK5+ER?PR? tumor cells, and cohorts of endocrine therapy treated patient clinical samples. Experiments will 1) Determine the mechanism of PR induction of the CK5 gene through an essential progesterone responsive element (PRE); 2) Evaluate how progestins convert single ER+PR+ cells to ER?PR? mammosphere-forming CSCs; and 3) Define if blocking CK5+ cells during endocrine therapy will reduce recurrence. These studies have implications for individual tumor cell plasticity, and could explain how progestins accelerate tumor growth during hormone replacement therapies. They also seek to explain if CK5+ ER?PR? cells contribute to the increased recurrence of some luminal tumors. Our long term goal is to implement strategic and simultaneous management of heterogeneous luminal breast cell populations with the ultimate goal of reducing the incidence of endocrine refractory breast cancer.

Public Health Relevance

The goal of this study is to determine how hormones regulate a subpopulation of cancer stem cells within estrogen receptor (ER) and progesterone receptor (PR) positive breast cancers. Studies seek to determine the molecular mechanism of how hormones increase these cancer stem cells, and how they contribute to tumor progression and recurrence. They also seek to uncover if blocking this subpopulation during endocrine therapy can reduce recurrence of ER positive breast cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140985-07
Application #
9249487
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2011-01-01
Project End
2021-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
7
Fiscal Year
2017
Total Cost
$295,821
Indirect Cost
$103,446
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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