Epithelial membrane protein 3 (EMP3) belongs to the peripheral myelin protein 22 kDa (PMP22) gene family, characterized by four transmembrane domains and widespread expression across various human tissues and organs [1]. It has regulatory roles in immune cells like T cells and macrophages, and is involved in critical signaling pathways such as HER-2/PI3K/Akt, MAPK/ERK, and TGF-beta/Smad. Also, it is associated with cell cycle regulation, cellular proliferation, and apoptosis [1].

In glioblastoma, EMP3 knockout (KO) studies have shown significant insights. EMP3 KO enhances epidermal growth factor (EGF)-induced shuttling of EGFR into RAB7+ late endosomes, promoting EGFR degradation, and thus inhibiting the cyclin-dependent kinase CDK2 and EGFR-dependent and cell cycle transcriptional programs. This leads to reduced proliferation rates, blunted mitogenic response to EGF, and increased sensitivity to kinase inhibitors in EMP3 KO cells [2]. In glioblastoma, EMP3 also mediates tumor-associated macrophage (TAM) infiltration and T cell exclusion. Elevated EMP3 is accompanied by high PD-L1 expression, abundant M2 TAM recruitment, and lack of T cell infiltration. EMP3 is a potent protein in M2 TAM polarization and recruitment, and it suppresses T cell infiltration by inhibiting macrophage secretion of CXCL9 and CXCL10 [3].

In breast cancer, loss-of-function studies demonstrated that EMP3 inhibits breast cancer cell S-phase entry, DNA replication, DNA damage repair, and stem-like properties. It also blocks Akt-mTOR signaling activation and induces autophagy, and sensitizes breast cancer cells to the DNA-damaging drug Adriamycin [4].

In conclusion, EMP3 plays diverse roles in various biological processes. In glioblastoma, it is involved in oncogenic signaling and immune modulation, while in breast cancer, it appears to have a tumor-suppressive role in processes related to DNA replication and repair. The use of gene knockout models in these studies has been crucial in revealing these functions, providing a better understanding of the role of EMP3 in disease-related biological processes.