The Roles Of MiR-183-96-182Cluster And MiR-135a In Breast Cancer

Human growth hormone (hGH) plays critical roles in pubertal mammary gland growth, development and sexual maturation. Accumulated studies have reported that autocrine/paracrine hGH is an orthotopically expressed oncoprotein that promotes normal mammary epithelial cell oncogenic transformation. Autocrine/paracrine hGH has also been reported to promote mammary epithelial cell epithelial-mesenchymal transition (EMT) and invasion. However, the underlying mechanism remains largely obscure. miRNAs are reported to involved in regulation of multiple cellular functions of cancer. To determine whether autocrine/paracrine hGH promotes EMT and invasion through modulation miRNA expression, we performed microarray profiling using MCF-7cells stably expressing wild type or a translation deficient hGH gene and identified miR-183-96-182as an autocrine/paracrine hGH regulated miRNA cluster. Forced expression of miR-183-96-182conferred epithelioid MCF-7cells with a mesenchymal phenotype and promoted invasive behavior in vitro and dissemination in vivo. Moreover, we observed that miR-183-96-182promoted EMT and invasion by directly and simultaneously suppressing Breast Cancer Metastasis Suppressor1-like (BRMS1L) gene expression. miR-96and miR-182also targeted GHR, providing a potential negative feedback loop in the hGH-GHR signaling pathway. We further demonstrated that autocrine/paracrine hGH stimulated miR-183-96-182expression and facilitated EMT and invasion via STAT3and STAT5signaling. Consistent with elevated expression of autocrine/paracrine hGH in metastatic breast cancer tissue, miR-183-96-182expression was also remarkably enhanced. Hence, we delineate the roles of the miR-183-96-182cluster and elucidate a novel hGH-GHR-STAT3/STAT5-miR-183-96-182-BRMS1L-ZEB1/E47-EMT/invasion axis, which provides further understanding of the mechanism of autocrine/paracrine hGH stimulated EMT and invasion in breast cancer.The somatic genetic profiling of cancer tissues has a potential for providing enormous information to the personalized prediction of clinical treatment response and outcome. Further revealing the underlying molecular mechanisms are crucial for integrating the genomic information with the clinical decision. Herein we report MIR135A1, a microRNA gene at chromosome3p21.1, is frequently lost and associated with poor prognosis in primary breast cancer. Reduced expression of miR-135a, in part due to the genomic loss, conduces to aggressive behaviors of cancer cells in vitro and in vivo. We demonstrated estrogen receptor (ERa) directly controls pri-miR-135a-1transcription, and anti-estrogen treatment of breast cancer cells leads to irreversibly reduced expression of miR-135a. The decrease of miR-135a is sufficient and required for ERa positive cells to acquire tamoxifen resistance via modulating ERa-ERK-AKT cross-talk. miR-135a directly targets ESR1, ESRRA and NCOA1, forming a negative feedback to regulate ERa pathway. PIM2, MRAS and LCP1are identified as another three targets of miR-135a, which contribute to the aggressive phenotype and tamoxifen resistance in miR-135a down-regulated breast cancer cells. Thus, the finding of the balance between miR-135a with ERa-ERK-AKT signaling, which is often destroyed during mammary carcinoma progression, could potentially benefit the patients with acquired tamoxifen resistance.