Screening of the entire let-7 family of miRNAs by in situ hybridization identified let-7g as the only member, the diminished expression of which was significantly associated with lymph node metastasis and poor survival in breast cancer patients. Abrogation of let-7g expression in otherwise non-metastatic mammary carcinoma cells elicited rapid metastasis from the orthotopic location, through preferential targets, GAB2 and FN1, and consequent activation of p44/42 MAPK and specific matrix metalloproteinases. Treatment with estrogen or EGF specifically reduced the expression of mature let-7g through activation of p44/42 MAPK and subsequently stimulated expression of GAB2 and FN1, which in turn promoted tumor invasion. We thus identify let-7g as a unique member of the let-7 miRNA family which can serve as a prognostic biomarker in breast cancer and also propose a paradigm utilized by specific signaling molecules via let-7g to cooperatively promote breast cancer invasion and metastasis. Thus, let-7 family members neither possess equivalent clinicopathologic correlation nor function in breast cancer.

PMID: 21868760 [PubMed - as supplied by publisher] Source: National Library of Medicine.