Abstract
The oncogenic isoform of HER2, HER2Δ16, is expressed with HER2 in nearly 50% of HER2 positive breast tumors where HER2Δ16 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 HER2Δ16 oncogene alters microRNA expression to promote endocrine resistance. With the goal of identifying microRNA suppressors of HER2Δ16 oncogenic activity we investigated the contribution of altered microRNA expression to HER2Δ16 mediated tumorigenesis and trastuzumab resistance. Using a gene array strategy comparing microRNA expression profiles of MCF-7 to MCF-7/HER2Δ16 cells, we found that expression of HER2Δ16 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/HER2Δ16 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/HER2Δ16 cell migration through a mechanism involving suppression of the miR-7 target gene EGFR. In contrast, miR-7 inhibition of MCF-7/HER2Δ16 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/HER2Δ16 cells to trastuzumab. Our results demonstrate that reestablished miR-7 expression abolishes HER2Δ16 induced cell proliferation and migration while sensitizing HER2Δ16 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 HER2Δ16 driven breast cancer.
Highlights
Breast cancer is the most commonly diagnosed cancer in North American women and the second leading cause of cancer related deaths
We have recently shown that HER2D16 expression alters expression of miR-15a/16 and miR-342 to promote endocrine resistance of breast tumor cells [5, 6]
Altered miR-7 and epidermal growth factor receptor (EGFR) expression was continuously monitored and remained stable in the MCF-7/miR-7KD and MCF-7/HER2D16H/miR-7 cell lines for greater than 20 cell passages. These results suggest that selective suppression of miR-7 and subsequent restoration of EGFR expression occurs in response to ectopic HER2D16 expression in MCF-7 cells
Summary
Breast cancer is the most commonly diagnosed cancer in North American women and the second leading cause of cancer related deaths. 90% of patients with tumor expression of HER2D16 present with disseminated metastatic disease. Breast tumors that overexpress wild-type HER2, but lack detectable HER2D16 expression, are significantly associated with favorable clinicopathological markers including lymph node negative cancer [4]. When overexpressed in breast tumor cells, HER2D16 promotes resistance to multiple endocrine therapies [5, 6], as well as, the HER2 targeted therapy trastuzumab [4]. These clinical and experimental observations suggest that HER2D16 expression drives HER2 positive breast cancer to an aggressive and therapeutic refractory metastatic disease. The molecular basis of HER2D16 oncogenic activity remains to be deciphered, recent studies indicate that HER2D16 expression alters microRNA (miR) expression to evade therapeutic intervention [5, 6]
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