Tumor-Promoting Properties of TMEM9A in Breast Cancer Progression <i>via</i> Activating the Wnt/β-Catenin Signaling Pathway

Abstract

Breast cancer (BC) is the most generally diagnosed cancer and the driving cause of cancer-related death. Transmembrane (TMEM) proteins have been reported to serve as prognostic indicators in a variety of cancers, and it can offer therapeutic targets for carcinoma. However, the function of TMEM in BC remains unclear. In this study, TMEM9A, a member of TMEM family, was screened as the candidate gene after analyzing the profiles of GSE42568 and GEPIA-BRCA database via bioinformatic method. The upregulated expression of TMEM9A was confirmed in BC samples compared with the paired normal tissues. Hence, we speculated that TMEM9A might promote BC progression. To test the hypothesis, we performed a series of loss/gain-of-function experiments and found that BC cells with TMEM9A deletion inhibited cell proliferation, migration, and invasion along with induced apoptosis. Conversely, TMEM9A overexpression reversed the trend. Mechanically, TMEM9A knockdown blocked the Wnt/β-catenin signaling pathway as evidenced by the increased adenomatous polyposis coli (APC) expression and decreased β-catenin, cyclin D1, and axis inhibition protein 2 (AXIN2) expression. Furthermore, over-activation of the Wnt/β-catenin pathway by transfecting BC cells with β-Catenin-S33Y (β-Catenin tyrosine for serine at codon 33) plasmids reversed the effects caused by TMEM9A knockdown. In conclusion, TMEM9A may play a tumor-promoting role in BC progression via activating the Wnt/β-catenin signaling pathway. Therefore, TMEM9A may be an effective therapeutic option for BC.