SCARA5 plays a critical role in the progression and metastasis of breast cancer by inactivating the ERK1/2, STAT3, and AKT signaling pathways

Scavenger receptor class A member 5 (SCARA5) is a candidate anti-oncogene in several malignancies. However, whether SCARA5 is a suppressor gene in breast cancer and its role in breast cancer cell growth and metastasis remain to be determined. Here, we investigated the biological functions of SCARA5 in the progression and metastasis of breast cancer and explored the underlying mechanisms. A total of 65 breast cancer patients and three cell lines (ZR-75-30, MCF-7, and MDA-MB-231) were analyzed in the study. RT-qPCR, western blotting, and immunohistochemistry were used to detect mRNA and protein expression, and lymphatic vessel density (LVD) and microvessel density (MVD). MTT, colony formation, TUNEL assays, invasion assays and Transwell assays, and flow cytometric analyses were used to evaluate the effect of SCARA5 on breast cancer cells. SCARA5 was significantly downregulated in breast cancer tissues and cells and significantly correlated with tumor size, histological grade, lymph node metastasis, pTNM stage, VEGF-A, VEGF-C, LVD, and MVD. SCARA5 overexpression significantly suppressed cell proliferation, colony formation, invasion, and migration, and induced G0/G1 arrest and apoptosis of ZR-75-30 cells. SCARA5 decreased the phosphorylation of ERK1/2, AKT, and STAT3, and downregulated downstream signaling effectors, including MMP-2, 3, and 9, VEGF-A, VEGF-C, Bax, Cyclin B1, Cyclin D1, and Cyclin E1, and upregulated E-cadherin, Bcl-2, and caspase 3. SCARA5 is associated with multiple signaling pathways and plays a critical role in the progression and metastasis of breast cancer. The present results provide the first evidence that SCARA5 inhibits lymphangiogenesis by downregulating VEGF-C, thereby inhibiting breast cancer lymphatic metastasis.