| Breast cancer is one of the most prevalent and serious malignancies affecting women worldwide, and the incidence of breast cancer is booming, especially in the developing countries, such as China, causing thousands of deaths and enormous economic losses annually. To our current knowledge, breast cancer is a genetic disease, whose initiation and progression is a multistep process that involves varied genetic and epigenetic modifications.microRNAs (miRNAs) are small, endogenous non-coding RNAs consisting of21-24nucleotides, which repress gene expression post-transcriptionally via recognizing complementary target sites in the3’untranslated regions (3’UTRs) of cognate mRNAs. In view of that each miRNA controls dozen of distinct targets, it is believed that>650human miRNAs are able to regulate over one-third of the mRNA species encoded in human genome. Accumulating evidence reveals that miRNAs are involved in the regulation of varies of biological processes and their dysregulation is associated with various human diseases, such as cancer. Previous studies have identified let-7as a notable miRNA family which function as tumor suppressor genes. However, several groups recently reported that members of let-7family have different expression levels and functional roles in different types of cancer or in different stages of the same type of cancer, and sometimes they may function as oncogenes. Thus, in this study, we mainly focused on the different roles and corresponding mechanisms of let-7family members in breast cancer invasion and metastasis.We first screened the entire let-7family of9mature miRNAs in archived breast cancer specimens (n=86) and breast tissue specimens from patients with benign breast diseases (n=21) using in situ hybridization, and found that let-7g was the only member, the diminished expression of which was significantly associated with lymph node metastasis and poor survival in breast cancer patients. Then, by use of the wound healing assays, transwell migration and invasion assays and models of orthotopic injection and tail vein injection into nude mice, we observed that let-7g depletion in low-invasive MCF-7cells led to an obvious increase in cell migration and invasion, whereas forced expression of let-7g in the highly invasive MDA-MB-231cells resulted in significant reduction in cell migration and invasion. Further experiments revealed that abrogation of let-7g expression in otherwise non-metastatic mammary carcinoma cells promoted invasion and metastasis through preferential targets, GAB2 and FN1, and consequent activation of p44/42MAPK and specific matrix metalloproteinases. Moreover, we identified let-7g as the most efficient let-7family members to repress the3’UTRs of GAB2and FN1. Finally, we observed that treatment with estrogen or EGF specifically reduced the expression of mature let-7g through activation of p44/42MAPK and subsequently stimulated expression of GAB2and FN1, which in turn promoted tumor invasion. We thus identify let-7g as a unique member of the let-7miRNA family which can serve as both diagnostic and prognostic biomarkers in breast cancer and also propose a paradigm (E2/EGF→p44/42MAPK→let-7g→AB2/FN1→p44/42MAPK-MMP-2/MMP-9cascade) utilized by specific signaling molecules via let-7g to cooperatively promote breast cancer invasion and metastasis.Hence, let-7family members neither possess equivalent clinicopathologic correlation nor function in breast cancer. In this issue, we observed the pivotal role of reduced let-7g expression in breast cancer invasion and metastasis, and unraveled the intrinsic mechnisms by which let-7g possesses such a special role. Our study provides a novel diagnostic and prognostic biomarker in breast cancer, and also provides a new avenue toward understanding the mechanism of breast cancer metastasis and may facilitate in the development of potential therapeutics against breast cancer. |
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