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stigate the potential role of miR expression contributing to Indirubin-3′-oxime price HER2D16 driven tumorigenesis we compared global miR expression profiles between parental MCF-7 breast cancer cells and a MCF-7 cell line with ectopic expression of HER2D16 . Probing a LC Sciences miR array containing 837 unique human miRs we found that HER2D16 expression significantly altered the expression of 82 miRs with 16 miRs altered by 2-fold or greater. Of the 16 miRs altered in HER2D16 expressing cells at least three are consistent with a role in HER2D16 driven tumorigenesis. For example, we have previously shown that the suppression of miR-342-3p contributes to endocrine resistance of HER2D16 expressing breast tumor cells. Upregulation of miR-125b expression has been suggested to regulate chemosensitivity of breast tumor cells. For the current studies we focused our attention on the 4.8 fold suppression of miR-7. Significantly, miR-7 is 5 / 16 MiR-7 Suppresses HER2D16 Oncogenic Activity Fig. 1. Altered miR expression in response to HER2D16 expression in MCF-7 cells. Heat PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19683408 map of all miRs significantly altered by 1.2-fold or greater or by 2-fold or greater in MCF-7/HER2D16H cells when compared to MCF-7/pcDNA cells. Data represents four independent RNA samples for each cell line. doi:10.1371/journal.pone.0114419.g001 6 / 16 MiR-7 Suppresses HER2D16 Oncogenic Activity considered a potent tumor suppressor miR and has been shown to regulate expression of multiple target genes in breast tumor cells. Although the exact mechanism mediating HER2D16 suppression of miR-7 remains to be established our previously published data suggests that the Jumonji/ ARID1 B transcriptional repressor may play a role. JARID1B is a breast oncogene most dramatically overexpressed in HER2 positive breast tumors. We have shown that JARID1B transcriptionally represses the expression of multiple tumor suppressor miRs in breast tumor cell lines. Significantly, over 90% of the JARID1B regulated miRs, including miR-7, are also similarly altered by HER2D16 expression. Although experimental validation is required, these observations raise the possibility that JARID1B transcriptionally represses multiple miRs, including miR-7, in HER2D16 expressing breast tumor cells. MiR-7 suppresses breast tumor cell proliferation and HER2D16 driven cell migration We have previously shown that HER2D16 expression significantly potentiates MCF-7 cell proliferation, migration/invasion, xenograft tumor formation, and resistance to multiple therapeutic interventions; whereas, expression of wild-type HER2 failed to enhance a single tumorigenic property of MCF-7 cells. Given the potent oncogenic activity of HER2D16 and the clinical association of HER2D16 with metastatic breast cancer we investigated the impact of miR-7 activity on HER2D16 driven tumorigenesis. MiR-7 expression was suppressed by 3 to 5-fold in two independent HER2D16 expressing MCF-7 cell lines when compared to the MCF-7 parental cell line. Modulation of miR-7 expression PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19683970 had a dramatic impact on the miR-7 target gene EGFR with the highest levels of EGFR expression associated with reduced levels of miR-7 in the MCF-7/HER2D16H, and MCF-7/HER2D16M1 cell lines. Consistent with these observations, knockdown of miR-7 expression in the MCF-7 cell line, MCF-7/miR-7KD, resulted in enhanced EGFR expression whereas reintroduced miR-7 expression in the MCF-7/HER2D16H cell line, MCF-7/HER2D16H/miR-7, resulted in suppressed EGFR expression. A similar but less dramatic impact o