MicroRNA-7 inhibits multiple oncogenic pathways to suppress HER2?16 mediated breast tumorigenesis and reverse trastuzumab resistance.

ABSTRACT: The oncogenic isoform of HER2, HER2?16, is expressed with HER2 in nearly 50% of HER2 positive breast tumors where HER2?16 drives metastasis and resistance to multiple therapeutic interventions including tamoxifen and trastuzumab. In recent years microRNAs have been shown to influence multiple aspects of tumorigenesis and tumor cell response to therapy. Accordingly, the HER2?16 oncogene alters microRNA expression to promote endocrine resistance. With the goal of identifying microRNA suppressors of HER2?16 oncogenic activity we investigated the contribution of altered microRNA expression to HER2?16 mediated tumorigenesis and trastuzumab resistance. Using a gene array strategy comparing microRNA expression profiles of MCF-7 to MCF-7/HER2?16 cells, we found that expression of HER2?16 significantly altered expression of 16 microRNAs by 2-fold or more including a 4.8 fold suppression of the miR-7 tumor suppressor. Reestablished expression of miR-7 in the MCF-7/HER2?16 cell line caused a G1 cell cycle arrest and reduced both colony formation and cell migration activity to levels of parental MCF-7 cells. Suppression of miR-7 in the MCF-7 cell line resulted in enhanced colony formation activity but not cell migration, indicating that miR-7 suppression is sufficient to drive tumor cell proliferation but not migration. MiR-7 inhibited MCF-7/HER2?16 cell migration through a mechanism involving suppression of the miR-7 target gene EGFR. In contrast, miR-7 inhibition of MCF-7/HER2?16 cell proliferation involved a pathway where miR-7 expression resulted in the inactivation of Src kinase independent of suppressed EGFR expression. Also independent of EGFR suppression, reestablished miR-7 expression sensitized refractory MCF-7/HER2?16 cells to trastuzumab. Our results demonstrate that reestablished miR-7 expression abolishes HER2?16 induced cell proliferation and migration while sensitizing HER2?16 expressing cells to trastuzumab therapy. We propose that miR-7 regulated pathways, including EGFR and Src kinase, represent targets for the therapeutic intervention of refractory and metastatic HER2?16 driven breast cancer.

SUBMITTER: Huynh FC 

PROVIDER: S-EPMC4273950 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature