Progesterone Receptors Drive Advanced Breast Cancer Phenotypes Including Circulating Tumor- and Stem-Like Cell Expansion in the Context of ESR1 Mutation

Authors

• Thu H. Truong
• Noelle E. Gillis
• Amy R. Dwyer
• Rosemary J. Huggins
• Kyla M. Hagen
• Sai Harshita Posani
• Nuri A. Temiz
• Carlos Perez Kerkvliet, Thomas Jefferson University
• Ellie M. Piepgras
• Julie H. Ostrander
• Geoffrey L. Greene
• Carol A. Lange

Document Type

Article

Publication Date

4-7-2026

Comments

This article is the author’s final published version in npj Breast Cancer, Volume 12, Issue 1, 2026, Article number 75.

The published version is available at https://doi.org/10.1038/s41523-026-00939-8. Copyright © The Author(s) 2026.

Abstract

Endocrine therapy resistance remains a major challenge in the treatment of advanced estrogen receptor positive (ER+) breast cancer. This can be driven by acquired mutations in the estrogen receptor gene (ESR1), such as Y537S or D538G, that results in constitutive estrogen-independent ER activity. Progesterone receptors (PR) are important modifiers of ER activity, in part via direct binding. We previously showed that PR mediates expansion of cancer stem-like cell (CSC) populations. In this study, we sought to define whether PR function changes in the context of ESR1 mutations. PR readily interacted with wild type (WT), but not Y537S or D538G ERs. RNA-seq and ChIP-seq studies demonstrated that ER+ breast cancer models expressing Y537S ER exhibited a distinct response to progesterone. CSC populations were enhanced in Y537S ER+ cells compared to WT ER+ cells. PR knockdown demonstrated that this property required PR expression but was unresponsive to antiprogestins. Moreover, we identified PR-dependent transcriptional programs such as the unfolded protein response (UPR) that can be leveraged to target CSCs in Y537S ESR1-mutant breast cancer. Our findings demonstrate an interplay between PR and mutant ER function and provide insight into PR-driven pathways that can be exploited as potential therapeutic avenues in ER+ breast cancer.

Recommended Citation

Truong, Thu H.; Gillis, Noelle E.; Dwyer, Amy R.; Huggins, Rosemary J.; Hagen, Kyla M.; Posani, Sai Harshita; Temiz, Nuri A.; Perez Kerkvliet, Carlos; Piepgras, Ellie M.; Ostrander, Julie H.; Greene, Geoffrey L.; and Lange, Carol A., "Progesterone Receptors Drive Advanced Breast Cancer Phenotypes Including Circulating Tumor- and Stem-Like Cell Expansion in the Context of ESR1 Mutation" (2026). Department of Urology Faculty Papers. Paper 101.
https://jdc.jefferson.edu/urologyfp/101

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

41946751

Language

English