High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer
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) meta...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472300832X |
| _version_ | 1797731102717116416 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Xiaoyong Fu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T11:53:54Z |
| format | Article |
| id | doaj.art-9ae29d74241a427e80d1e8022dc30c52 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-12T11:53:54Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-9ae29d74241a427e80d1e8022dc30c522023-08-31T05:01:44ZengElsevierCell Reports2211-12472023-08-01428112821High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancerXiaoyong Fu0Resel Pereira1Chia-Chia Liu2Carmine De Angelis3Martin J. Shea4Sarmistha Nanda5Lanfang Qin6Tamika Mitchell7Maria L. Cataldo8Jamunarani Veeraraghavan9Vidyalakshmi Sethunath10Mario Giuliano11Carolina Gutierrez12Balázs Győrffy13Meghana V. Trivedi14Ofir Cohen15Nikhil Wagle16Agostina Nardone17Rinath Jeselsohn18Mothaffar F. Rimawi19C. Kent Osborne20Rachel Schiff21Lester 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 authorLester 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, USALester 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, USALester 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, ItalyLester 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, USALester 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, USALester 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, USALester 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, USALester 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, ItalyLester 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, USALester 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, USALester 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, ItalyDepartment of Pathology, Baylor College of Medicine, Houston, TX 77030, USADepartment of Bioinformatics, Semmelweis University, 1085 Budapest, Hungary; RCNS Cancer Biomarker Research Group, Institute of Enzymology, Magyar Tudósok körútja 2, 1117 Budapest, HungaryLester 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, USADepartment 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, IsraelDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02210, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USADepartment 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, USADepartment 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, USALester 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, USALester 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, USALester 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S221112472300832XCP: Cancer |
| spellingShingle | 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 High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer Cell Reports CP: Cancer |
| title | High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer |
| title_full | High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer |
| title_fullStr | High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer |
| title_full_unstemmed | High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer |
| title_short | High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer |
| title_sort | high foxa1 levels induce er transcriptional reprogramming a pro metastatic secretome and metastasis in endocrine resistant breast cancer |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S221112472300832X |
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