FOXA1 upregulation promotes enhancer and transcriptional reprogramming in endocrine-resistant breast cancer
Abstract
Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic transcription factors. Hyperactive FOXA1 signaling due to gene amplification or overexpression has been reported in estrogen receptor-positive (ER + ) endocrine-resistant metastatic breast cancer. However, the molecular mechanisms by which FOXA1 up-regulation promotes these processes and the key downstream targets of the FOXA1 oncogenic network remain elusive. Here, we demonstrate that FOXA1 overexpression in ER + breast cancer cells drives genome-wide enhancer reprogramming to activate prometastatic transcriptional programs. Up-regulated FOXA1 employs superenhancers (SEs) to synchronize transcriptional reprogramming in endocrine-resistant breast cancer cells, reflecting an early embryonic development process. We identify the hypoxia-inducible transcription factor hypoxia-inducible factor-2α (HIF-2α) as the top high FOXA1-induced SE target, mediating the impact of high FOXA1 in activating prometastatic gene sets and pathways associated with poor clinical outcome. Using clinical ER + /HER2 − metastatic breast cancer datasets, we show that the aberrant FOXA1/HIF-2α transcriptional axis is largely nonconcurrent with the ESR1 mutations, suggesting different mechanisms of endocrine resistance and treatment strategies. We further demonstrate the selective efficacy of an HIF-2α antagonist, currently in clinical trials for advanced kidney cancer and recurrent glioblastoma, in reducing the clonogenicity, migration, and invasion of endocrine-resistant breast cancer cells expressing high FOXA1. Our study has uncovered high FOXA1-induced enhancer reprogramming and HIF-2α–dependent transcriptional programs as vulnerable targets for treating endocrine-resistant and metastatic breast cancer.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 11, 2019
- Source ID
- 10.1073/pnas.1911584116
Entities
People
- Agostina Nardone
- Bert W. O’malley
- Britta Weigelt
- C. Kent Osborne
- Carmine De Angelis
- Carolina Gutierrez
- Gary C. Chamness
- Jamunarani Veeraraghavan
- Jorge S Reis-Filho
- Lanfang Qin
- Maria L. Cataldo
- Mothaffar F Rimawi
- Myles A. Brown
- Nikhil Wagle
- Ofir Cohen
- Pier Selenica
- Qin Feng
- Rachel Schiff
- Resel Pereira
- Rinath Jeselsohn
- Sarmistha Nanda
- Sepideh Mehravaran
- Vidyalakshmi Sethunath
- Xiaoyong Fu
Organizations
- Baylor College of Medicine
- Broad Institute
- Congressionally Directed Medical Research Programs
- Harvard Medical School
- Memorial Sloan Kettering Cancer Center
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- Stand Up to Cancer
- Susan G. Komen for the Cure
- The Breast Cancer Research Foundation
- University of Houston