Functional Analysis of Adhesion <scp>GPCR</scp> Latrophilin 2 (<scp>ADGRL2</scp>) in <scp>MDA</scp>‐<scp>MB</scp>‐231 Human Breast Cancer Cells

The tumor microenvironment strongly influences cancer cell behavior, including growth, migration, invasiveness, and gene expression dynamics. Adhesion G protein-coupled receptors (aGPCR) play critical roles in cell-cell or cell-extracellular matrix (ECM) interaction. This study aims to investigate the functions and elucidate signaling of Latrophilin-2 (LPHN2), an aGPCR, in breast cancer progression using MDA-MB-231 cells. LPHN2-deficient MDA-MB-231 cells exhibited decreased invasion-like sphere structure in 3D culture, reduced proliferation, diminished adhesion to collagen I, and impaired migration activity. Reporter assays and pharmacological inhibition experiments revealed that the C-terminal fragment (CTF) of LPHN2 activates SRE- and CREB-mediated gene transcription while activating ROCK and PKA signaling pathways. Additionally, downregulation of Gα12/13 and Gαs reduced cell migration in both wild-type and CTF-overexpressing LPHN2-knockout cells, demonstrating that LPHN2 couples to Gα12/13 and Gαs signaling pathways. These findings highlight the functional significance of LPHN2 in breast cancer cell behavior and provide potential therapeutic targets for breast cancer intervention.