Regulation of growth, invasion and metabolism of breast ductal carcinoma through CCL2/CCR2 signaling interactions with MET receptor tyrosine kinases.

ABSTRACT: With over 60,000 cases diagnosed annually in the US, ductal carcinoma in situ (DCIS) is the most prevalent form of early-stage breast cancer. Because many DCIS cases never progress to invasive ductal carcinomas (IDC), overtreatment remains a significant problem. Up to 20% patients experience disease recurrence, indicating that standard treatments do not effectively treat DCIS for a subset of patients. By understanding the mechanisms of DCIS progression, we can develop new treatment strategies better tailored to patients. The chemokine CCL2 and its receptor CCR2 are known to regulate macrophage recruitment during inflammation and cancer progression. Recent studies indicate that increased CCL2/CCR2 signaling in breast epithelial cells enhance formation of IDC. Here, we characterized the molecular mechanisms important for CCL2/CCR2-mediated DCIS progression. Phospho-protein array profiling revealed that CCL2 stimulated phosphorylation of MET receptor tyrosine kinases in breast cancer cells. Co-immunoprecipitation and proximity ligation assays demonstrated that CCL2-induced MET activity depended on interactions with CCR2 and SRC. Extracellular flux analysis and biochemical assays revealed that CCL2/CCR2 signaling in breast cancer cells enhanced glycolytic enzyme expression and activity. CRISPR knockout and pharmacologic inhibition of MET revealed that CCL2/CCR2-induced breast cancer cell proliferation, survival, migration and glycolysis through MET-dependent mechanisms. In animals, MET inhibitors blocked CCR2-mediated DCIS progression and metabolism. CCR2 and MET were significantly co-expressed in patient DCIS and IDC tissues. In summary, MET receptor activity is an important mechanism for CCL2/CCR2-mediated progression and metabolism of early-stage breast cancer, with important clinical implications.

SUBMITTER: Acevedo DS 

PROVIDER: S-EPMC9010752 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature