Breast cancer recurrence remains a significant risk among node-positive patients. Breast cancer stem or stem- like cells (BCSCs herein) disseminate and evade first-line therapies, and account for high mortality among patients with advanced endocrine-resistant disease. The objective of this proposal is to define the signaling pathways that drive the emergence and expansion of endocrine-resistant BCSCs, with the goal of blocking epigenetic events to specifically target this population of tumor cells. Filling this knowledge gap will pave the way for intervention that blocks BCSCs and ensures long-term disease-free survival. We identified the chromatin- associated, steroid receptor (SR) transcriptional coregulator, PELP1, as a mediator of BCSC expansion. Utilizing mass spectrometry, we identified the steroid receptor coactivator-3, SRC-3 (also known as AIB1), as a novel and preferential interactor with cytoplasmic relative to nuclear PELP1. Notably, PELP1 increased activation of SRC-3 in BC cells, while SRC-3 knockdown blocked PELP1-induced BCSC expansion, suggesting an essential role for active PELP1/SRC3 complexes in BCSC outgrowth. In follow-up studies, we found that cytoplasmic PELP1 promotes the phosphorylation of SRC-3 on Thr24 and Ser857. Work of others has implicated SRC-3 pSer857 in breast cancer metastasis as a key substrate of the bifunctional kinase/phosphatase known as PFKFB4. In related work, we showed that PELP1 forms constitutive transcriptional complexes with both estrogen (ER) and progesterone (PR) receptors in breast cancer models and patient tumors; a scaffolding action of PR- B, but not progesterone, was required for ER phosphorylation and regulation of genes by ER/PR/PELP1 complexes, including gene sets important for tamoxifen resistance. Herein, we hypothesize that ER/PR/PELP1/SRC-3 complexes recruit and amplify key cytoplasmic signaling pathways that mediate epigenetic events required for chromatin remodeling and reprogramming of steroid receptor (SR)-regulated transcriptomes required for expansion of therapy resistant BCSC populations. We will test this hypothesis in breast cancer models and in the following Specific Aims: ? Identify PELP1/SRC-3-activated signaling pathways essential for BCSC expansion and therapy resistance. ? Determine how PELP1/SRC-3 complexes reprogram SR transcriptomes. ? Determine if PELP1/SRC-3/SR cooperation promotes tumorigenesis in vivo. Current therapies primarily inhibit BC proliferation, but fail to adequately target BCSCs. Understanding the mechanisms of PELP1/SRC-3/SR signaling and reversible epigenetic regulation of BCSCs will reveal novel therapies that target the required components of this complex (i.e. other than ER) or downstream signaling molecules and prevent or reverse this process, thus significantly impacting on the longevity of patients with metastatic breast cancer.

Public Health Relevance

Breast cancer recurrence remains a significant health burden for women undergoing long-term endocrine therapy following diagnosis with luminal (ER+) breast cancer. The goal of these studies is to reveal how steroid hormone receptors become dysregulated during metabolic and cell fate transitions that contribute to breast cancer progression, escape from ER-targeted therapies, and dissemination as long-lived cancer stem or stem- like cells capable of successful metastatic spread. Non-ER mediators of these reversible epigenetic events are highly targetable as part of future combination therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA236948-01A1
Application #
9884189
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Johnson, Ronald L
Project Start
2019-12-01
Project End
2024-11-30
Budget Start
2019-12-01
Budget End
2020-11-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455