TMEM132A affects proliferation, invasion, and apoptosis via the β-catenin-dependent Wnt signaling in breast cancer.

Breast cancer continues to pose a significant health threat to women globally, highlighting the urgent need for novel therapeutic targets. The Wnt/β-catenin pathway plays an important role in tissue homeostasis. The Wnt/β-catenin signaling pathway frequently contributes to serious diseases, particularly cancer, through its dysregulation [1]. Transmembrane protein 132A (TMEM132A) serves as a potential regulator of the canonical Wnt pathway and is related to cancer progression. Nevertheless, the function of TMEM132A in breast cancer remains inadequately verified (Gao et al., 2023) [2]. In the present work, we initially confirmed the substantial overexpression of TMEM132A in breast cancer by analyzing TCGA, GEO, and GTEx datasets. This finding was further validated in breast cancer cell lines, where its expression correlated with unfavorable prognosis. TMEM132A overexpression was found to augment proliferation, migration, and invasion, and inhibit apoptosis in breast cancer cell lines (MDA-MB-231 and MCF-7), as demonstrated through functional validation, while its knockdown induced opposite effects. Mechanistically, TMEM132A knockdown reduced the expression of key Wnt pathway components, including Wnt3a, β-catenin, c-Myc, and Cyclin D1. Notably, nuclear and cytoplasmic fractionation assays demonstrated that TMEM132A promotes the nuclear accumulation of β-catenin, indicating enhanced activation of Wnt/β-catenin signaling. Furthermore, treatment with the Wnt inhibitor C59 attenuated the tumor-promoting effects induced by TMEM132A overexpression. Our findings establish that TMEM132A is a critical regulator of this signaling axis in cancer progression, highlighting its potential as a therapeutic target for breast cancer.