GPR107: A key driver of breast cancer invasion and metastasis through collagen IV modulation.

Abstract

Breast cancer is a leading cause of cancer-related death in women, and the development of effective treatments for advanced disease remains a critical challenge. Metastasis, the spread of cancer cells to distant sites, is the major cause of mortality in breast cancer. We identified a novel role for the G protein-coupled receptor 107 (GPR107) in promoting breast cancer invasion and metastasis. Furthermore, we found that GPR107 mediates a reduction in collagen Ⅳ (COL4), a key component of the extracellular matrix (ECM) that normally restricts tumor cell invasion. This reduction in COL4 levels was associated with GPR107 mediating the Clathrin-mediated endocytosis of COL4 from the ECM, an increase in matrix metalloproteinase 2 (MMP2) production to degrade COL4 in the ECM, and a decrease in COL4 production. Mechanistically, we identified GPR107 as a key mediator of the ERK/STAT3 pathway activation through β-arrestin, leading to increased expression of MMP2 and suppression of COL4 gene transcription, effectively promoting invasion and metastasis in breast cancer cells. These findings suggest that GPR107 could serve as a promising biomarker for predicting breast cancer malignancy and a potential therapeutic target for preventing and treating metastatic disease.