Activin-like kinase 5 (ALK5) inactivation in the mouse uterus results in metastatic endometrial carcinoma. Author Diana Monsivais, Jia Peng, Yibin Kang, Martin Matzuk Publication Year 2019 Type Journal Article Abstract The endometrial lining of the uterine cavity is a highly dynamic tissue that is under the continuous control of the ovarian steroid hormones, estrogen and progesterone. Endometrial adenocarcinoma arises from the uncontrolled growth of the endometrial glands, which is typically associated with unopposed estrogen action and frequently occurs in older postmenopausal women. The incidence of endometrial cancer among younger women has been rising due to increasing rates of obesity, a major risk factor for the disease. The transforming growth factor β (TGFβ) family is a highly conserved group of proteins with roles in cellular differentiation, proliferation, and cancer. Inactivating mutations in the genes encoding the TGFβ cell surface receptors ( and ) have been detected in various human cancers, indicating that a functional TGFβ signaling pathway is required for evading tumorigenesis. In this study, we present a mouse model with conditional inactivation of activin receptor-like kinase 5 (ALK5) in the mouse uterus using progesterone receptor cre (" cKO") that develops endometrial adenocarcinoma with metastasis to the lungs. The cancer and metastatic lung nodules are estrogen dependent and retain estrogen receptor α (ERα) reactivity, but have decreased levels of progesterone receptor (PR) protein. The endometrial tumors develop only in cKO mice that are mated to fertile males, indicating that TGFβ-mediated postpartum endometrial repair is critical for endometrial function. Overall, these studies indicate that TGFβ signaling through TGFBR1/ALK5 in the endometrium is required for endometrial homeostasis, tumor suppression, and postpartum endometrial regeneration. Keywords Animals, Disease Models, Animal, Mice, Humans, Signal Transduction, Female, Carcinogenesis, Neoplasm Metastasis, Transforming Growth Factor beta, Lung Neoplasms, Adenocarcinoma, Endometrial Neoplasms, Endometrium, Receptor, Transforming Growth Factor-beta Type I, Receptor, Transforming Growth Factor-beta Type II, Uterus Journal Proc Natl Acad Sci U S A Volume 116 Issue 9 Pages 3883-3892 Date Published 2019 Feb 26 ISSN Number 1091-6490 DOI 10.1073/pnas.1806838116 Alternate Journal Proc Natl Acad Sci U S A PMCID PMC6397539 PMID 30655341 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML