Cip2a/MIR-301a feedback loop promotes cell proliferation and invasion of triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype and lacks effective targeted therapies. Cancerous inhibitor of protein phosphatase 2A (Cip2a) is an oncogene that is known to inhibit PP2A tumor suppressor activity in human malignancies. We previously demonstrated that Cip2a is a novel target for the treatment of TNBC. However, the functional roles of Cip2a in TNBC progression are still not fully characterized. In this study, we identified that MIR-301a is a novel target of Cip2a in TNBC cell lines by MIRNA microarray analysis. We found that Cip2a increases E2F1 expression, which in turn transcriptional activates MIR-301a by occupying the MIR-301a host gene SKA2 promoter. Moreover, we found that MIR-301a level is significantly increased in TNBC tissues, and up-regulation of MIR-301a is responsible for Cip2a-induced cell proliferation and invasion of TNBC cells. Furthermore, MIR-301a feedback promotes the expression of Cip2a via activation of ERK/CREB signaling. Together, our study suggests an auto-regulatory feedback loop between Cip2a and MIR-301a and this auto-regulatory loop might play an important role in TNBC progression.