Data from Pivotal Role of Reduced <i>let-7g</i> Expression in Breast Cancer Invasion and Metastasis

Abstract

<div>Abstract<p>Screening of the entire <i>let-7</i> family of microRNAs (miRNA) by <i>in situ</i> hybridization identified <i>let-7g</i> 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 <i>let-7g</i> expression in otherwise nonmetastatic mammary carcinoma cells elicited rapid metastasis from the orthotopic location, through preferential targets, Grb2-associated binding protein 2 (GAB2) and fibronectin 1 (FN1), and consequent activation of p44/42 mitogen-activated protein kinase (MAPK) and specific matrix metalloproteinases. Treatment with estrogen or epidermal growth factor specifically reduced the expression of mature <i>let-7g</i> through activation of p44/42 MAPK and subsequently stimulated expression of GAB2 and FN1, which, in turn, promoted tumor invasion. We thus identify <i>let-7g</i> as a unique member of the <i>let-7</i> miRNA family that can serve as a prognostic biomarker in breast cancer and also propose a paradigm used by specific signaling molecules via <i>let-7g</i> to cooperatively promote breast cancer invasion and metastasis. Thus, <i>let-7</i> family members neither possess equivalent clinicopathologic correlation nor function in breast cancer. <i>Cancer Res; 71(20); 6463–74. ©2011 AACR</i>.</p></div>