TY - JOUR
T1 - Activin-like kinase 5 (ALK5) inactivation in the mouse uterus results in metastatic endometrial carcinoma
AU - Monsivais, Diana
AU - Peng, Jia
AU - Kang, Yibin
AU - Matzuk, Martin M.
N1 - Funding Information:
We thank Drs. John Lydon and Francesco DeMayo for providing the PRcre mouse line, Dr. Stefan Karlsson for providing the Alk5flox/flox mouse line, and Dr. Donna M. Coffey (Houston Methodist Hospital) for her analysis of the uterine histology.These studies were supported by Eunice Kennedy Shriver National Institute of Child Health and Human Development Grants R01-HD032067 and R01-HD033438 (to M.M.M.), K99-HD096057 (to D.M.), the Institutional Research and Academic Career Development Award K12-GM084897 (to D.M.), the New Jersey Commission on Cancer Research Fellowship (to J.P.), the Brewster Foundation (Y.K.), and National Institutes of Health Grant R01-CA212410 (to Y.K.). D.M. holds a Postdoctoral Enrichment Program Award from the Burroughs Wellcome Fund. CT analysis of the mice was performed in the Mouse Metabolism and Phenotyping Core at Baylor College of Medicine with funding from National Institutes of Health Grants UM1HG006348 and R01DK114356.
Publisher Copyright:
© 2019 National Academy of Sciences. All Rights Reserved.
PY - 2019/2/26
Y1 - 2019/2/26
N2 - 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.
AB - 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.
KW - Endometrial cancer
KW - Estrogen receptor
KW - Knockout mouse
KW - TGFβ
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U2 - 10.1073/pnas.1806838116
DO - 10.1073/pnas.1806838116
M3 - Article
C2 - 30655341
AN - SCOPUS:85062010231
SN - 0027-8424
VL - 116
SP - 3883
EP - 3892
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 9
ER -