Deregulated miRNAs in Hereditary Breast Cancer Revealed a Role for miR-30c in Regulating KRAS Oncogene

Abstract

Aberrant miRNA expression has been previously established in breast cancer and has clinical relevance. However, no studies so far have defined miRNAs deregulated in hereditary breast tumors. In this study we investigated the role of miRNAs in hereditary breast tumors comparing with normal breast tissue. Global miRNA expression profiling using Exiqon microarrays was performed on 22 hereditary breast tumors and 15 non-tumoral breast tissues. We identified 19 miRNAs differentially expressed, most of them down-regulated in tumors. An important proportion of deregulated miRNAs in hereditary tumors were previously identified commonly deregulated in sporadic breast tumors. Under-expression of these miRNAs was validated by qRT-PCR in additional 18 sporadic breast tumors and their normal breast tissue counterparts. Pathway enrichment analysis revealed that deregulated miRNAs collectively targeted a number of genes belonging to signaling pathways such as MAPK, ErbB, mTOR, and those regulating cell motility or adhesion. In silico prediction detected KRAS oncogene as target of several deregulated miRNAs. In particular, we experimentally validated KRAS as a miR-30c target. Luciferase assays confirmed that miR-30c binds the 3′UTR of KRAS transcripts and expression of pre-miR-30c down-regulated KRAS mRNA and protein. Furthermore, miR-30c overexpression inhibited proliferation of breast cancer cells. Our results identify miRNAs associated to hereditary breast cancer, as well as miRNAs commonly miss-expressed in hereditary and sporadic tumors, suggesting common underlying mechanisms of tumor progression. In addition, we provide evidence that KRAS is a target of miR-30c, and that this miRNA suppresses breast cancer cell growth potentially through inhibition of KRAS signaling.

Low expression of microRNA-30c promotes prostate cancer cells invasion involved in downregulation of KRAS protein

“…It was previously reported that miR-30c can regulate KRAS in breast cancer (23), and the present study revealed that KRAS was downregulated in miR-30c overexpression cells compared with control cells. This indicated that KRAS may be a common target of miR-30c in different types of tumors.…”

“…It was previously reported that KRAS is a target of miR-30c in breast cancer (23). The present study aimed to investigate whether miR-30c can control KRAS in prostatic cancer.…”

Coffee reduces KRAS expression in Caco-2 human colon carcinoma cells via regulation of miRNAs

“…Let-7a miRNA inhibits cell proliferation in the lung cancer cell line, 95D, by regulating the translation of KRAS mRNA (16). The miRNA miR-30c suppresses breast cancer cell growth, potentially through the inhibition of KRAS signaling (17). Similarly, in coffee extract-treated Caco-2 cells, elevated miR-30c and miR-96 may suppress KRAS expression, potentially by affecting KRAS mRNA stability (17).…”

“…The miRNA miR-30c suppresses breast cancer cell growth, potentially through the inhibition of KRAS signaling (17). Similarly, in coffee extract-treated Caco-2 cells, elevated miR-30c and miR-96 may suppress KRAS expression, potentially by affecting KRAS mRNA stability (17). Further studies are needed to clarify the mechanisms underlying regulation of miRNA expression by coffee extract.…”

Down-regulation of miRNA-30c predicts poor prognosis in Colorectal Cancer patients

“…Recently, it was reported that human miRNA-30c was down-regulated in non-small cell lung cancer (NSCLC) and breast cancer [18,19], this informed that miRNA-30c functioned as a tumor suppressor. Quintavalle et al reported that miRNA-30c could suppress apoptosis of lung cancer cells [20].…”