# SRC-3/PELP1 complexes drive stem-like phenotypes in luminal breast cancer

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $465,438

## Abstract

Abstract
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.

## Key facts

- **NIH application ID:** 10737629
- **Project number:** 5R01CA236948-05
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Carol A Lange
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $465,438
- **Award type:** 5
- **Project period:** 2019-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10737629

## Citation

> US National Institutes of Health, RePORTER application 10737629, SRC-3/PELP1 complexes drive stem-like phenotypes in luminal breast cancer (5R01CA236948-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10737629. Licensed CC0.

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