Conditional abrogation of transforming growth factor‐β receptor 1 in PTEN‐inactivated endometrium promotes endometrial cancer progression in mice

Abstract

Although a putative role for TGF beta (TGFB) signaling in the pathogenesis of human endometrial cancer has long been proposed, the precise function of TGFB signaling in the development and progression of endometrial cancer remains elusive. Depletion of PTEN in the mouse uterus causes endometrial cancer. To identify the potential role of TGFB signaling in endometrial cancer, we simultaneously deleted TGFB receptor 1 (Tgfbr1) and Pten in the mouse uterus using Cre-recombinase driven by the progesterone receptor (termed Ptend/d; Tgfbr1d/d). We found that Ptend/d; Tgfbr1d/d mice developed severe endometrial lesions that progressed more rapidly compared with those resulting from conditional deletion of Pten alone, suggesting that TGFB signaling synergizes with PTEN to suppress endometrial cancer progression. Remarkably, the Ptend/d; Tgfbr1d/d mice developed distant pulmonary metastases, leading to significantly reduced life span. The development of metastasis and accelerated tumor progression in Ptend/d; Tgfbr1d/d mice are associated with increased production of pro-inflammatory chemokines, enhanced cancer cell motility evidenced by myometrial invasion and disruption, and altered tumor microenvironment characterized by recruitment of tumor-associated macrophages. Thus, conditional deletion of Tgfbr1 in PTEN-inactivated endometrium leads to a disease that recapitulates invasive and lethal human endometrial cancer. This mouse model may be valuable for preclinical testing of new cancer therapies, particularly those targeting metastasis, one of the hallmarks of cancer and a major cause of death in endometrial cancer patients.

Tumor-suppressive signaling in the uterus

“…Monsivais et al (2) report that Alk5 cKO mice develop metastatic endometrial tumors. It should be emphasized that loss of ALK5 promotes endometrial oncogenesis only in female mice being continuously mated with fertile males, consistent with our previous finding that nulliparous female Alk5 cKO mice are cancer-free (17). Notably, the main metastatic site of endometrial cancer in Alk5 cKO mice is the lung, which contains a recombined Alk5 allele (2).…”

“…A more recent study using mice with uterine epithelial cell-specific deletion of Pten also suggests a tumorsuppressive function of uterine TGF-β signaling (18). Monsivais et al (2) extend the previous findings (17) by showing that ablation of ALK5 per se can lead to the development of metastatic endometrial cancer, contingent on a second event of pregnancy/parturition-induced endometrial remodeling. This exciting observation inspired further experimentation using a unilateral oviduct ablation model, in which only uterine horns with an intact oviduct develop cancer (2).…”

“…Notably, the main metastatic site of endometrial cancer in Alk5 cKO mice is the lung, which contains a recombined Alk5 allele (2). We previously disrupted Alk5 in phosphatase and tensin homolog (PTEN)-depleted endometrium (17). Loss of ALK5 exacerbates progression of endometrial cancer induced by PTEN inactivation and promotes pulmonary metastasis (17).…”

“…We previously disrupted Alk5 in phosphatase and tensin homolog (PTEN)-depleted endometrium (17). Loss of ALK5 exacerbates progression of endometrial cancer induced by PTEN inactivation and promotes pulmonary metastasis (17). A more recent study using mice with uterine epithelial cell-specific deletion of Pten also suggests a tumorsuppressive function of uterine TGF-β signaling (18).…”

The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten

“…These results suggest a role for TGFβ in epithelial proliferation [ 48 ]. Pten and TGFβr1 double knockout mice using Pgr-Cre driver show severe endometrial lesions with disrupted myometrial layers and pulmonary metastasis [ 49 ], suggesting a role for TGFβr1 in cancer progression. Mice with uterine stromal TGFβr1 -deletion using Amhr2-Cre show enhanced proliferation in both luminal and glandular epithelia [ 50 ], suggesting TGFβ signaling is involved in epithelial-stromal interactions.…”