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Proc Natl Acad Sci U S A. 2019 Feb 26;116(9):3883-3892. doi: 10.1073/pnas.1806838116. Epub 2019 Jan 17.

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

Monsivais D1,2,3, Peng J1,3,4, Kang Y4, Matzuk MM5,2,3,6,7,8,9.

Author information

1
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030.
2
Center for Drug Discovery, Baylor College of Medicine, Houston, TX 77030.
3
Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX 77030.
4
Department of Molecular Biology, Princeton University, Princeton, NJ 08544.
5
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030; mmatzuk@bcm.edu.
6
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030.
7
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030.
8
Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030.
9
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030.

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.

KEYWORDS:

TGFβ; endometrial cancer; estrogen receptor; knockout mouse

Comment in

PMID:
30655341
PMCID:
PMC6397539
DOI:
10.1073/pnas.1806838116
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: D.M. and T.E.S. are coauthors on a 2015 Commentary article.

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