Integrative pipeline to profile and target endocrine therapy-insensitive cell populations in ER+ breast cancer

Authors

Semina, S., Huggins, R. J., Zhao, H., Yanagihara, K., Sheinin, M., Macias, V., Alani, F., Feferman, L., Kajdacsy-Balla, A. A., Tonetti, D., Hoskins, K., Frasor, J., Coloff, J. L.

Abstract

Up to 40% of patients with estrogen receptor positive breast cancer will experience relapse, either while on endocrine therapy (ET) or after ET is completed. A major contributor to ET failure is the presence of ET-insensitive cell populations within tumors. Here, we developed an analytical pipeline to systematically identify and target these populations by integrating single-cell RNA sequencing of ER+ tumors from the FELINE clinical trial with functional validation in a panel of patient-derived xenograft organoid models. We found that ET-insensitive cells are detected in all tumors regardless of clinical response and exhibit higher transcriptional heterogeneity than ET-sensitive populations. Using our pipeline, we identified and validated new therapeutic options that target patient-specific and shared ET-insensitive populations. Our integrated workflow provides a robust platform for identifying and targeting ET-insensitive cells and offers a translational framework to develop precision medicine approaches to improve outcome in breast cancer patients.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 17 Sep 2026.

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