PTEN suppresses epithelial\u2013mesenchymal transition and cancer stem cell activity by downregulating Abi1

Yanmei Qi,Joshua Chao,Leonard Y Lee,Jie Liu,Shaohua Li,Mark P Scheuerman,Saum A Rahimi

doi:10.1038/s41598-020-69698-1

Abstract

The epithelial–mesenchymal transition (EMT) is an embryonic program frequently reactivated during cancer progression and is implicated in cancer invasion and metastasis. Cancer cells can also acquire stem cell properties to self-renew and give rise to new tumors through the EMT. Inactivation of the tumor suppressor PTEN has been shown to induce the EMT, but the underlying molecular mechanisms are less understood. In this study, we reconstituted PTEN-deficient breast cancer cells with wild-type and mutant PTEN, demonstrating that restoration of PTEN expression converted cancer cells with mesenchymal traits to an epithelial phenotype and inhibited cancer stem cell (CSC) activity. The protein rather than the lipid phosphatase activity of PTEN accounts for the reversal of the EMT. PTEN dephosphorylates and downregulates Abi1 in breast cancer cells. Gain- and loss-of-function analysis indicates that upregulation of Abi1 mediates PTEN loss-induced EMT and CSC activity. These results suggest that PTEN may suppress breast cancer invasion and metastasis via dephosphorylating and downregulating Abi1.

Highlights

The epithelial–mesenchymal transition (EMT) is an embryonic program frequently reactivated during cancer progression and is implicated in cancer invasion and metastasis
cancer stem cell (CSC) markers have negative predictive value for these inhibitors[34]. These results strongly argue for the existence of important PI3K-independent activities that contribute to the role of PTEN in suppression of CSC activity and cancer progression[10,35,36,37,38,39,40,41,42]
Abi[1] serves as a substrate for PTEN and is significantly upregulated in PTEN-deficient breast cancer cells. shRNAmediated knockdown of Abi[1] in PTEN-deficient breast cancer cells reverses the EMT and reduces CSCs. These results suggest that PTEN loss may induce the EMT and increase CSC activity through dephosphorylation and upregulation of Abi[1]

Summary

Introduction

The epithelial–mesenchymal transition (EMT) is an embryonic program frequently reactivated during cancer progression and is implicated in cancer invasion and metastasis. Gain- and loss-of-function analysis indicates that upregulation of Abi[1] mediates PTEN loss-induced EMT and CSC activity These results suggest that PTEN may suppress breast cancer invasion and metastasis via dephosphorylating and downregulating Abi[1]. Recent studies have shown that the EMT is responsible for the generation of breast cancer stem cells (CSCs), which are resistant to conventional therapy and contribute to tumor metastasis and r ecurrence[6,7,8] Independent of these findings, mutations in BRCA1/2, TP53 and PTEN have emerged as high-penetrance susceptibility genes and are clinically relevant for determining breast cancer risk and prognosis[9]. These results suggest that PTEN loss may induce the EMT and increase CSC activity through dephosphorylation and upregulation of Abi[1]

Methods

Results

Conclusion