期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 132, 期 12, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI157574
关键词
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资金
- National Cancer Institute [5P30CA142543]
- NIH [R01CA272667, R01CA13718 1, R01CA245294]
- Cancer Prevention & Research Insti-tute of Texas [RP190454]
- Department of Defense [W81XWH-21-1-0114]
FOXA2 gene has a higher mutation rate in aggressive variants of endometrial cancers (ECs). It controls endometrial epithelial gene expression programs regulating cell proliferation, adhesion, and endometrial-epithelial transition. The inactivation of both Foxa2 and PI3K signaling leads to lethal ECs with complete penetrance. FOXA2 plays a role in tumor suppression through modification of enhancer activity and regulates specific target genes.
FOXA2 encodes a transcription factor mutated in 10% of endometrial cancers (ECs), with a higher mutation rate in aggressive variants. FOXA2 has essential roles in embryonic and uterine development. However, FOXA2???s role in EC is incompletely understood. Functional investigations using human and mouse EC cell lines revealed that FOXA2 controls endometrial epithelial gene expression programs regulating cell proliferation, adhesion, and endometrial-epithelial transition. In live animals, conditional inactivation of Foxa2 or Pten alone in endometrial epithelium did not result in ECs, but simultaneous inactivation of both genes resulted in lethal ECs with complete penetrance, establishing potent synergism between Foxa2 and PI3K signaling. Studies in tumor-derived cell lines and organoids highlighted additional invasion and cell growth phenotypes associated with malignant transformation and identified key mediators, including Myc and Cdh1. Transcriptome and cistrome analyses revealed that FOXA2 broadly controls gene expression programs through modification of enhancer activity in addition to regulating specific target genes, rationalizing its tumor suppressor functions. By integrating results from our cell lines, organoids, animal models, and patient data, our findings demonstrated that FOXA2 is an endometrial tumor suppressor associated with aggressive disease and with shared commonalities among its roles in endometrial function and carcinogenesis.
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