# Targeting Oncogenic PELP1/SRC-3 Signaling Complexes in ER+ Breast Cancer

> **NIH NIH K22** · UNIVERSITY OF MINNESOTA · 2024 · $201,744

## Abstract

Project Summary
Breast cancer is the most commonly diagnosed cancer in women, with estrogen receptor positive (ER+) breast
cancers accounting for 75% of cases. Endocrine therapies directed at blocking ER action are highly effective;
however, 40% of women with ER+ tumors develop resistance and progress to metastatic disease. ER+ tumors
relapse late, and tumor cells can remain quiescent for years to decades. Progress in the treatment of metastatic
breast cancer is limited by strategies that primarily target rapidly proliferating tumor cells. Contributing factors to
advanced disease progression include breast cancer stem cells (CSC), which are poorly proliferative and exist
as minority populations in therapy resistant tumors. We identified SRC-3 (steroid receptor [SR] co-activator 3)
as a novel cytoplasmic binding partner of PELP1. Similar to SRC-3, PELP1 is an ER co-activator, and
dynamically shuttles between the nucleus and cytoplasm to act as a nuclear co-activator and cytoplasmic
scaffolding protein for growth factor and steroid receptors. PELP1 is primarily nuclear in normal breast, but
increased cytoplasmic localization of PELP1 is an oncogenic event that promotes disease progression by
unknown mechanisms. We showed PELP1/SRC-3 cytoplasmic complexes drive breast CSC phenotypes and
genes associated with pro-survival in ER+ breast cancer models. SRC-3 inhibition disrupts complex formation
and cytoplasmic PELP1-induced tumorspheres. Top candidates identified from RNA-seq analysis include
PFKFB family members, which are bi-functional kinase/phosphatases that have roles in cancer metabolism and
CSC biology. PFKFB3/-4 co-purified with PELP1/SRC-3 complexes; inhibition of PFKFB3/-4 blocked
PELP1/SRC-3 complex formation and biology. Remarkably, PELP1/SRC-3 CSC biology is phenocopied in
tamoxifen-resistant (TamR) and paclitaxel-resistant (TaxR) models. Herein, we hypothesize that PELP1/SRC-3
complexes amplify signaling inputs to PFKFB family members that mediate altered metabolic pathways required
for resistant ER+ tumor cell populations. We will: 1) identify signaling pathways essential for PELP1/SRC-3
driven therapy resistance using mass cytometry, and 2) determine the therapeutic benefits of targeting
PELP1/SRC-3/PFKFB complexes in vivo to block cancer progression and metastasis. Our long-term objectives
are to identify non-ER therapeutic targets that can be developed as combination strategies to eliminate therapy
resistant tumor cells in ER+ breast cancer. During the K22 award, we expect to define the molecular links
between cancer cell metabolism and oncogenic events in breast cancer progression, metastasis, and examine
the benefits of targeting this pathway to impair late recurrence. This proposal will provide a solid foundation for
the candidate’s goal of moving towards translational cancer research during her transition to independence.
Delineating the key players will fundamentally redefine standard care options to target therapy-resistant
pop...

## Key facts

- **NIH application ID:** 10755239
- **Project number:** 5K22CA248615-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Thu Ha Truong
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $201,744
- **Award type:** 5
- **Project period:** 2023-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10755239

## Citation

> US National Institutes of Health, RePORTER application 10755239, Targeting Oncogenic PELP1/SRC-3 Signaling Complexes in ER+ Breast Cancer (5K22CA248615-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10755239. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*