Loss of Cdh1 and Pten Accelerates Cellular Invasiveness and Angiogenesis in the Mouse Uterus1

Abstract

E-cadherin (CDH1) is a cell adhesion molecule that coordinates key morphogenetic processes regulating cell growth, cell proliferation, and apoptosis. Loss of CDH1 is a trademark of the cellular event epithelial to mesenchymal transition, which increases the metastatic potential of malignant cells. PTEN is a tumor-suppressor gene commonly mutated in many human cancers, including endometrial cancer. In the mouse uterus, ablation of Pten induces epithelial hyperplasia, leading to endometrial carcinomas. However, loss of Pten alone does not affect longevity until around 5 mo. Similarly, conditional ablation of Cdh1 alone does not predispose mice to cancer. In this study, we characterized the impact of dual Cdh1 and Pten ablation (Cdh1(d/d) Pten(d/d)) in the mouse uterus. We observed that Cdh1(d/d) Pten(d/d) mice died at Postnatal Days 15-19 with massive blood loss. Their uteri were abnormally structured with curly horns, disorganized epithelial structure, and increased cell proliferation. Co-immunostaining of KRT8 and ACTA2 showed invasion of epithelial cells into the myometrium. Further, the uteri of Cdh1(d/d) Pten(d/d) mice had prevalent vascularization in both the endometrium and myometrium. We also observed reduced expression of estrogen and progesterone receptors, loss of cell adherens, and tight junction molecules (CTNNB1 and claudin), as well as activation of AKT in the uteri of Cdh1(d/d) Pten(d/d) mice. However, complex hyperplasia was not found in the uteri of Cdh1(d/d) Pten(d/d) mice. Collectively, these findings suggest that ablation of Pten with Cdh1 in the uterus accelerates cellular invasiveness and angiogenesis and causes early death.

Concurrent deletion of 16q23 and PTEN is an independent prognostic feature in prostate cancer

“…A cooperative effect with PTEN inactivation has indeed earlier been suggested for the loss of the cell–cell adhesion molecule CDH1 (E‐cadherin), which is often downregulated or mutated in breast and gastric cancers and has also been proposed as a metastasis suppressor in prostate cancer . In one study in mouse uterus, combined knockdown of CDH1 and PTEN , but not CDH1 or PTEN alone, resulted in invasion of epithelial cells into the myometrium and massive angiogenesis, resembling the situation in high‐grade endometrial carcinomas . Although CDH1 is no “classical” haplo‐insufficient gene like PTEN , the fact that all the deletions of 16q were heterozygous supports a model in which compound haplo‐insufficiency of one or more 16q gene(s) (possibly including CDH1 ) in addition to PTEN loss exerts a massive tumor promoting effect.…”

The impact of microRNA-mediated PI3K/AKT signaling on epithelial-mesenchymal transition and cancer stemness in endometrial cancer

“…Homozygous deletion of PTEN in PTEN +/− mice leads to rapid formation of EC [43]. Consistent with this, conditional ablation of PTEN in mouse uterus is sufficient to activate the PI3K/AKT pathway and accelerate cancer cell invasiveness [44]. Furthermore, diminished AKT1 activity dramatically inhibits endometrial tumorigenesis caused by PTEN deficiency [45].…”

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

“…Interestingly, high dose progestin therapy has been shown to reverse pre-existing PTEN inactivated endometrial latent precursors and endometrial hyperplasia in some women (Orbo et al 2006). Lindberg et al (2013) generated a mouse model in which PTEN and Cdh1 were conditionally ablated in the uterus. Deletion of both the genes induced EMT phenotype and accelerated features of neoplastic transformation in the uterus by inducing myometrial invasion, proliferation, massive angiogenesis, and loss of steroid hormone receptors as well as Akt activation.…”