Cell Reports (Aug 2023)
High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer
- Xiaoyong Fu,
- Resel Pereira,
- Chia-Chia Liu,
- Carmine De Angelis,
- Martin J. Shea,
- Sarmistha Nanda,
- Lanfang Qin,
- Tamika Mitchell,
- Maria L. Cataldo,
- Jamunarani Veeraraghavan,
- Vidyalakshmi Sethunath,
- Mario Giuliano,
- Carolina Gutierrez,
- Balázs Győrffy,
- Meghana V. Trivedi,
- Ofir Cohen,
- Nikhil Wagle,
- Agostina Nardone,
- Rinath Jeselsohn,
- Mothaffar F. Rimawi,
- C. Kent Osborne,
- Rachel Schiff
Affiliations
- Xiaoyong Fu
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Corresponding author
- Resel Pereira
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- Chia-Chia Liu
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Carmine De Angelis
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
- Martin J. Shea
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Sarmistha Nanda
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Lanfang Qin
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Tamika Mitchell
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Maria L. Cataldo
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
- Jamunarani Veeraraghavan
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Vidyalakshmi Sethunath
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Mario Giuliano
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
- Carolina Gutierrez
- Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA
- Balázs Győrffy
- Department of Bioinformatics, Semmelweis University, 1085 Budapest, Hungary; RCNS Cancer Biomarker Research Group, Institute of Enzymology, Magyar Tudósok körútja 2, 1117 Budapest, Hungary
- Meghana V. Trivedi
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pharmacy Practice and Translational Research, University of Houston, Houston, TX 77204, USA; Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX 77204, USA
- Ofir Cohen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva 84105, Israel
- Nikhil Wagle
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Agostina Nardone
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA
- Rinath Jeselsohn
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA
- Mothaffar F. Rimawi
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- C. Kent Osborne
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Rachel Schiff
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Corresponding author
- Journal volume & issue
-
Vol. 42,
no. 8
p. 112821
Abstract
Summary: 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.
