Center for Medical Ethics and Health Policy Staff Publications
Language
English
Publication Date
8-29-2023
Journal
Cell Reports
DOI
10.1016/j.celrep.2023.112821
PMID
37467106
PMCID
PMC12369075
PubMedCentral® Posted Date
8-22-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, the key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) enriched in ER+ endocrine-resistant (EndoR) cells. We identify Secretome14, a CGS subset encoding ER-dependent cancer secretory proteins, as a strong predictor for poor outcomes of ER+ BC. It is elevated in ER+ metastases vs. primary tumors, irrespective of ESR1 mutations. Genomic ER binding near Secretome14 genes is also increased in mutant ER-expressing or mitogen-treated ER+ BC cells and in ER+ metastatic vs. primary tumors, suggesting a convergent pathway including high growth factor receptor signaling in activating pro-metastatic secretome genes. Our findings uncover H-FOXA1-induced ER reprogramming that drives EndoR and metastasis partly via an H-FOXA1/ER-dependent secretome.
Keywords
CP: Cancer, breast cancer, cistrome, endocrine resistance, enhancer, epigenetic, estrogen receptor, forkhead box protein A1, metastasis, secretome, transcription factor
Published Open-Access
yes
Recommended Citation
Fu, Xiaoyong; Pereira, Resel; Liu, Chia-Chia; et al., "High FOXA1 Levels Induce Er Transcriptional Reprogramming, a Pro-Metastatic Secretome, and Metastasis in Endocrine-Resistant Breast Cancer" (2023). Center for Medical Ethics and Health Policy Staff Publications. 333.
https://digitalcommons.library.tmc.edu/med_ethics/333