miR-125a Induces HER2 Expression and Sensitivity to Trastuzumab in Triple-Negative Breast Cancer Lines
Lihi Ninio-Many, Elad Hikri, Burg-Golani Tamar, Salomon M. Stemmer, Ruth Shalgi, Irit Ben‐Aharon
Abstract
The EGFR/HER2 signaling network is an effective therapeutic target for HER2 positive cancers, which are known for their aggressive biological course. Evidence indicates that the EGFR/HER2 network plays a role in the aggressive basal-like subtype, as well. Here, we studied the potential role of miR-125a-3p as a modulator of the EGFR/HER2 pathway in basal-like breast cancer. Over-expression of miR-125a-3p reduced the migratory capability of MDA-MB-231 cells and though, led to an increase in the expression of ErbB2 transcript and protein. The induced ErbB2 responded to trastuzumab and underwent internalization and subsequent intra-lysosomal degradation. Trastuzumab treatment further reduced the migratory capability and induced apoptosis of the cells. An in-vivo mice model, which supported the in-vitro findings, showed a synergistic effect of miR-125a-3p and trastuzumab. Trastuzumab-treated-miR-125a-3p-induced tumors were significantly smaller than control- induced tumors. Our findings indicate that in the basal-like subtype of breast cancer, miR-125a-3p may act as a tumor suppressor. miR-125a-3p induces an increase in the expression of ErbB2 that may render the cells suitable for treatment by anti-HER2 therapies.