Transcriptional Downregulation of miR-4306 serves as a New Therapeutic Target for Triple Negative Breast Cancer

Rationale: Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor alpha (ER-α), human epidermal growth factor receptor 2 (HER2) and progesterone receptor (PR) expression, but the effect of lacking the three factors on TNBC is unclear. Whether loss of the three factors contributes to deregulate genes that participate in the progress of TNBC remains unknown. Methods: We performed microRNA arrays and comprehensive analysis to screen for miRNAs that are transcriptionally regulated by ER-α, HER2 and PR. Functional assays and molecular mechanism studies were used to investigate the role of miR-4306 in TNBC. An orthotopic mouse model of TNBC was used to evaluate the therapeutic potential of a cholesterol-conjugated miR-4306 mimic. Results: We found that miR-4306 is transcriptionally regulated by ER-α, HER2 and PR, and the downregulation of miR-4306 in TNBC is caused by the loss of ER-α, HER2 and PR. Clinically, low miR-4306 expression is strongly associated with lymph node metastasis and poor survival for TNBC. Upregulation of miR-4306 greatly suppresses TNBC cell proliferation, migration and invasion and abrogates angiogenesis and lymphangiogenesis in vitro. According to in vivo models, miR-4306 overexpression considerably inhibits TNBC growth, lung metastasis, angiogenesis and lymph node metastasis. Mechanistic analyses indicate that miR-4306 directly targets SIX1/Cdc42/VEGFA to inactivate the signaling pathways mediated by SIX1/Cdc42/VEGFA. Finally, the orthotopic mouse model of TNBC reveals that miR-4306 mimic can be used for TNBC treatment in combination with cisplatin. Conclusions: Our findings suggest that miR-4306 acts as a tumor suppressor in TNBC and is a potential therapeutic target for TNBC treatment.