{"doi":"10.1101/2025.05.19.654935","title":"Isoform-Specific Gene Regulation by Progesterone Receptors Drives Divergent Phenotypes in Breast Cancer Cells","abstract":"gene in breast tissue and play crucial roles in normal physiology and breast cancer progression. An imbalance in the expression ratio of these isoforms, favoring increased levels of PR-A, is common in breast cancer and is associated with resistance to tamoxifen in luminal A-type tumors. Notably, PRs have recently been implicated in promoting endocrine resistance and driving the expansion of cancer stem-like cell (CSC) populations. Despite this insight, the isoform-specific molecular and epigenetic mechanisms underlying PR action in estrogen receptor positive (ER+) breast cancers remain understudied. Phenotypic studies of T47D cell lines that express exclusively PR-A or PR-B showed that PR isoforms regulate divergent cell fates. PR-B-expressing cells have a higher proliferation rate, while PR-A-expressing cells produce more mammospheres. We profiled progesterone-driven gene expression in cells grown in both adherent (2D) and mammosphere (3D) growth conditions and found differential gene regulation by PR-A and PR-B that is consistent with the observed divergent phenotypes. Only the PR-A-driven gene signature of ER+ breast cancer cells maintained as non-adherent mammospheres robustly predicted poor clinical outcome in the METABRIC data set. We then performed CUT&RUN to identify the genomic binding patterns unique to each PR isoform and their suite of target genes. Our findings indicate that PR-A acts as a regulator of the cell cycle, while PR-B plays a pivotal role in metabolism and intracellular signaling. Our genomic profiling of PRs in this model system has unveiled novel isoform-specific functions of PR. This work has shifted our prior understanding of the role of PRs in gene regulation, offering potential insights for therapeutic interventions in ER+ breast cancer.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558015,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9507,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":355379,"name":"Thu H. Truong","orcid":"0000-0003-2394-551X","position":1,"is_corresponding":false},{"id":299735,"name":"Caroline H. Diep","orcid":"0000-0001-9011-6450","position":2,"is_corresponding":false},{"id":716320,"name":"Angela Spartz","orcid":null,"position":3,"is_corresponding":false},{"id":355380,"name":"Julie H. Ostrander","orcid":"0000-0002-5038-6875","position":4,"is_corresponding":false},{"id":299737,"name":"Carol A. Lange","orcid":"0000-0003-2751-3976","position":5,"is_corresponding":false},{"id":395403,"name":"Noelle E. Gillis","orcid":"0000-0002-0005-4194","position":0,"is_corresponding":true}],"reference_count":45,"raw_metadata":null,"created_at":"2026-07-19T02:55:21.727661Z","pmid":"40475467","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}