Estrogen-dependent regulation of lipolysis-stimulated lipoprotein receptor via G-protein-coupled estrogen receptor 1 in breast cancer malignancy

The lipolysis-stimulated lipoprotein receptor (LSR) is a tight junction protein implicated in tumor progression, yet its regulatory mechanisms in breast cancer (BC) remain unclear. We found that high LSR expression correlates with poor overall survival in BC patients. RNA interference-mediated LSR knockdown significantly reduced cell proliferation, migration, and invasion, indicating its contribution to malignant phenotypes. Our investigation into its regulation revealed that estrogen increases LSR expression in both ERα-positive and ERα-negative BC cells. This upregulation is mediated predominantly by the membrane-type G protein-coupled estrogen receptor GPER1 and requires activation of the ERK and PI3K-Akt pathways. Immunohistochemical analysis of surgical specimens confirmed that LSR and GPER1 are overexpressed in ductal carcinoma in situ and invasive ductal carcinoma compared with normal epithelium, with their expression levels showing a significant positive correlation. These findings identify an E2-GPER1-LSR signaling axis that promotes BC malignancy independently of nuclear ER status. Thus, LSR represents a promising prognostic biomarker and therapeutic target, and targeting the GPER1-mediated pathway may provide new insights into tumor progression and endocrine therapy response.