Chemokine (C-C motif) Ligand 2 Is Regulated Through the EGFR/Src Pathway in HER2-positive Breast Cancer Cells

Abstract

Background/Aim: Chemokine (C-C motif) ligand 2 (CCL2) influences growth and metastasis and is associated with poor prognosis in various cancers. However, the regulatory mechanism of CCL2 induction by human epidermal growth factor receptor 2 (HER2) is not fully understood in breast cancer. Thus, we investigated how CCL2 expression is regulated in HER2-positive (HER2+) breast cancer. Materials and Methods: A human cytokine array was performed to investigate the differential expression of cytokines by HER2 overexpression. Quantitative reverse transcription PCR, enzyme-linked immunosorbent assay and western blot were performed to detect the levels of mRNA and protein expression. Cell cycle and proliferation were analyzed by flow cytometry. Cell invasion was analyzed by Boyden chamber assay. Results: Our results showed that HER2 overexpression augmented CCL2 expression. Epidermal growth factor receptor (EGFR) and Src activities were increased in the HER2-overexpressed breast cancer cells. Interestingly, HER2-induced CCL2 expression could not be down-regulated by trastuzumab, while neratinib or saracatinib led to a decrease in the expression of CCL2 in HER2+ breast cancer cells. Conclusion: CCL2 expression is regulated through the EGFR/Src-dependent signaling in HER2+ breast cancer.