miR-135b Coordinates Progression of ErbB2-Driven Mammary Carcinomas through Suppression of MID1 and MTCH2
American Journal of Pathology
In an attempt to reveal deregulated miRNAs associated with the progression of carcinomas developed in BALB-neuT transgenic mice, we found increased expression of miR-135b during malignancy. Relevantly, we observed that miR-135b is up-regulated in basal or normal-like human breast cancers, and it correlates with patient survival and early metastatization. Therefore, we investigated its biological functions by modulating its expression (up-or down-regulation) in mammary tumor cells. Although no
... ells. Although no effect was observed on proliferation in cell culture and in orthotopically injected mice, miR-135b was able to control cancer cell stemness in a mammosphere assay, anchorage-independent growth in vitro, and lung cancer cell dissemination in mice after tail vein injections. Focusing on the miR-135b molecular mechanism, we observed that miR-135b controls malignancy via its direct targets, midline 1 (MID1) and mitochondrial carrier homolog 2 (MTCH2), as proved by biochemical and functional rescuing/ phenocopying experiments. Consistently, an anti-correlation between miR-135b and MID1 or MTCH2 was found in human primary tumor samples. In conclusion, our research led us to the identification of miR-135b and its targets, MID1 and MTCH2, as relevant coordinators of mammary gland tumor progression. (Am J Pathol 2013, 182: 2058e2070; http://dx. Breast cancer is one of the major health problems of the Western world. 1 Although the survival rate has improved with progress in screening and adjuvant therapies, one third of the patients present cancer recurrences 10 years after the diagnosis. 2 More than 90% of mortality from cancer is attributable to metastases and not to the primary tumor from which metastases arise. 3 Identification of the genetic and epigenetic changes foreshadowing metastasis is, thus, one of the highest priorities for translational cancer research. Although several protein-coding genes involved in malignancy have been identified and characterized, 4 noncoding genes, such as miRNAs that have been shown to regulate many aspects of the metastatic process, have to be characterized. 5 Several clinical studies show a correlation between miRNA expression and recurrence, development of metastasis, and/or survival. 6 miRNAs may also contribute to the metastatic program by modulating the structure of the tumor microenvironment, influencing the ability of cancer cells to move and survive. 7 Moreover, miRNAs are involved in the maintenance of the cancer stem cell (CSC) phenotype by connecting stemness and metastasis through regulation of epithelial-to-mesenchymal transition. 8 Global miRNA deregulation has been shown in breast cancer, 9e12 whereas specific miRNAs have been associated with clinicopathological features of breast tumors, such as estrogen and progesterone receptor expression, 13 tumor grade, 10 vascular invasion, or proliferation index. 14 As far as breast cancer is concerned, among other findings, reduced expression of miR-145, 15 miR-335, 16 and miR-126, 17 and overexpression of miR-10b, 18 miR-21, 19 and miR-210 20 were significantly associated with breast cancer invasion and metastasis.