Activin-like kinase 5 (ALK5) inactivation in the mouse uterus results in metastatic endometrial carcinoma.

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 (TGFBR1/ALK5 and TGFBR2) 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 ("Alk5 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 Alk5 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.

• Authors: Diana Monsivais, Jia Peng, Yibin Kang, Martin M Matzuk
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 116 Issue 9 Pg. 3883-3892 (02 26 2019) ISSN: 1091-6490 [Electronic] United States
• PMID: 30655341 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 the Author(s). Published by PNAS.

Chemical References

• Transforming Growth Factor beta
• Receptor, Transforming Growth Factor-beta Type I
• Receptor, Transforming Growth Factor-beta Type II
• Tgfbr1 protein, mouse
• Tgfbr2 protein, mouse

Topics

• Adenocarcinoma (genetics, pathology)
• Animals
• Carcinogenesis (genetics)
• Disease Models, Animal
• Endometrial Neoplasms (genetics, pathology)
• Endometrium (metabolism, pathology)
• Female
• Humans
• Lung Neoplasms (genetics, pathology, secondary)
• Mice
• Neoplasm Metastasis
• Receptor, Transforming Growth Factor-beta Type I (antagonists & inhibitors, genetics)
• Receptor, Transforming Growth Factor-beta Type II (genetics)
• Signal Transduction
• Transforming Growth Factor beta (genetics)
• Uterus (metabolism, pathology)