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.

PtenandDicer1loss causes poorly-differentiated endometrial adenocarcinoma in mice

“…Recent work has shown that dysregulation of TGFb signaling in the mouse uterus results in endometrial cancer (44,45). Members of the TGFb signaling pathways were targeted by a number of dysregulated miRNAs.…”

Tumor-suppressive signaling in the uterus

“…Unfortunately, the etiology of endometrial cancer remains poorly defined, hampering the design of effective diagnostic and therapeutic options for this disease. In PNAS, two exciting studies from the Matzuk laboratory (2,3) elegantly demonstrate that transforming growth factor β (TGF-β) signaling maintains endometrial homeostasis by suppressing cell overgrowth and oncogenesis. This action, the researchers show, is achieved through the TGF-β type I receptor (TGFBR1, or ALK5) and SMAD2/3.…”

“…Although mutation of the pathway components accounts for only a very small percentage of endometrial cancer, alteration in the signaling activity may be a common contributing factor (7)(8)(9)(10)(11)(12). To determine whether TGF-β signaling is involved in uterine physiology and cancer development, the Matzuk team took advantage of the Cre-loxP approach by generating mice with conditional knockout (cKO) of Alk5 [Monsivais et al (2)] or Smad2/3 [Kriseman et al (3)] in the uterus (Alk5 cKO or Smad2/3 cKO mice, respectively). The researchers used progesterone receptor (Pgr) Cre recombinase, which deletes genes in uterine epithelial, stromal, and myometrial cells (2,3).…”

“…To determine whether TGF-β signaling is involved in uterine physiology and cancer development, the Matzuk team took advantage of the Cre-loxP approach by generating mice with conditional knockout (cKO) of Alk5 [Monsivais et al (2)] or Smad2/3 [Kriseman et al (3)] in the uterus (Alk5 cKO or Smad2/3 cKO mice, respectively). The researchers used progesterone receptor (Pgr) Cre recombinase, which deletes genes in uterine epithelial, stromal, and myometrial cells (2,3). A major strength of these studies lies in the use of a genetic approach that conditionally disrupts two functionally related signaling molecules in the TGF-β pathway.…”

Reply to Liu et al.: ALK5-mediated tumor suppressor signaling through SMAD2 and SMAD3 in the uterus

“…Our recent publications in PNAS (1,2) describe the phenotypic effects of loss of activin-like kinase 5; transforming growth factor β receptor 1 (ALK5;TGFBR1) or Smad2 and Smad3 in the mouse uterus and are accompanied by a commentary by Li (3). Our conclusions are that this pathway acts as a tumor suppressor pathway, findings that are also supported by a recent paper (4).…”