# WNT pathway-driven anti-estrogen therapy resistance in breast cancer

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2024 · $537,544

## Abstract

Project Summary
The most aggressive cases of estrogen receptor-positive (ER+) breast cancers (BC) are diagnosed in young
women (<50 years-of-age). This project is focused on an understudied, aggressive, and therapy-resistant form
of ER+ BC that is characterized by predominantly ER+ luminal cancer cells interspersed with rare clusters of
ER-negative stem/progenitor cells that express the basal cytokeratin-5 (CK5). Patients with this mixed ‘lumino-
basal breast cancer’ (LBBC) phenotype represent a previously unrecognized population with unfavorable
prognosis. These tumors are aggressive due to their inherent ER-independent endocrine escape pathway, which
involves rapid expansion of the ER-/CK5+ cancer cell population in response to antiestrogen therapies.
Our data reveal that LBBC shares the younger age distribution and aggressive features of basal-like BC, a BC
subtype that is associated with pregnancy at early ages without breastfeeding – factors that are more prevalent
among Black and poorer women and thus may help explain disparities in BC. Intriguingly, the basal-like features
of LBBC are promoted by the pregnancy hormone progesterone and suppressed by the lactogenic
hormone prolactin. Compelling pilot data indicates that progestins or anti-estrogens expand the therapy-
resistant CK5+ stem/progenitor cell population in LBBC through a WNT11-PLZF-BCL6-dependent signaling
network and is reversed by prolactin.
The proposed studies will mechanistically test the general requirement of this WNT11-PLZF-BCL6 signaling
network required for antiestrogen and progesterone-driven expansion of the CK5+ cell population and LBBC
progression (Aim 1). Because the CK5+ cell population is often rare in untreated tumors, more robust diagnostic
classifiers for LBBC than CK5 alone will be developed (Aim 2). Finally, efforts will explore the efficacy of targeted
agents to disrupt this signaling network in vivo in preclinical models to provide rationale for new therapeutic
strategies for LBBC (Aim 3). In sum, we will mechanistically validate a newly discovered pathway that promotes
the therapy-resistant LBBC phenotype, develop better diagnostic methods, and explore therapeutic strategies to
overcome endocrine resistance of these tumors. The project holds potential for high impact progress that can
help reduce breast cancer mortality and morbidity.

## Key facts

- **NIH application ID:** 11012018
- **Project number:** 7R01CA267549-02
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Inna Chervoneva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $537,544
- **Award type:** 7
- **Project period:** 2022-12-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11012018

## Citation

> US National Institutes of Health, RePORTER application 11012018, WNT pathway-driven anti-estrogen therapy resistance in breast cancer (7R01CA267549-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11012018. Licensed CC0.

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