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miR-638, a Novel Tumor Suppressor for Triple-Negative Breast Cancer Open Access

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The Triple-negative breast cancer (TNBC) is known to be associated with poor outcome. Aberrantly expressed microRNAs (miRNAs) have emerged as an important set of biomarkers for breast cancer diagnosis and treatment. In our previous studies, we analyzed 8 breast cancer patient samples using microdissected Formalin-Fixed, Paraffin-Embedded (FFPE) tissues and miRNA microarray technologies. The miRNA expression profile was compared during the progression of breast cancer from normal, atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). Among the differentially expressed miRNAs during breast cancer progression, miR-638 is one of the differentially expressed miRNAs. In this study, we first sought to verify the expression of miR-638 in microdissected FFPE samples using the real-time qRT-PCR. Then we analyzed the expression of miR-638 in different breast cancer cell lines, which showed low expression in MDA-MB-231, Hs578T, MCF-7 and T47D compared to immortalized MCF-10A cells. We hypothesize that miR-638 may function as a tumor suppressor during breast cancer progression. To determine the role of miR-638 in both ER+ and ER- breast cancer cells, we transfected miR-638 mimic or scrambled oligos into MDA-MB-231 (ER-) , Hs578T (ER-), MCF-7 (ER+) and T47D (ER+) cells. We found that the proliferation rate was much lower in ER- cells compared to that in ER+ cells by MTT assays. In addition, Matrigel invasive analysis indicated that overexpressing miR-638 decreased invasion by 3~4 fold in TNBC cell lines, MDA-MB-231 and Hs578T. To elucidate the mechanism of its tumor suppressor activity, we used the TARGETSCAN-VERT to identify potential target genes of miR-638. Interestingly, BRCA1 is one of the direct targets of miR-638 among the 30 conservative target genes. We found that overexpression of miR-638 resulted in upregulation of BRCA1expression in TNBC cells, but not in homornal positive cells. These findings show that miR-638 may function as a tumor suppressor in TNBC, likely by upregulating BRCA1 tumor suppressor gene. Further functional analysis is contemplated to decipher the exact role of miR-638 in TNBC, which could become a therapeutic target.

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