title: Let-7a regulation of insulin-like growth factors in breast cancer.
abstract: Expression of certain microRNA genes is regulated by DNA methylation, which in turn affects the activities of their downstream molecules. Our previous study showed that methylated let-7a-3 was associated with low IGF-II expression and favorable prognosis of ovarian cancer. The roles of let-7a-3 methylation in breast cancer and in regulation of IGF expression in the tumor are still unknown. Let-7a-3 methylation, IGF mRNAs, and peptides were analyzed in 348 breast cancer samples using quantitative methylation-specific PCR, qRT-PCR, and ELISA, respectively. The associations of let-7a-3 methylation with IGFs, disease features, and patient survivals were analyzed. In vitro experiments were performed using HeLa cells transfected with let-7a precursors to assess the effect of let-7a on IGF expression. Let-7a-3 methylation was detected frequently in breast cancer. An inverse correlation between let-7a-3 methylation and IGF expression was observed in breast cancer, which was similar to that seen in ovarian cancer. Our in vitro experiment showed that let-7a could increase IGF expression in cancer cells which had low endogenous let-7a. Let-7a-3 methylation was also found to be associated with high grade tumors and ER- or PR-negative cancer. However, let-7a-3 methylation was not associated with disease-free survival or overall survival of breast cancer patients. The study provides further evidence in support of the notion that epigenetic regulation of let-7a-3 may affect the actions of IGFs in cancer. Let-7a may up-regulate the expression of IGFs in cancer cells, which is different from its inhibitory effects on other oncogenes.
authors.affiliation: Department of Epidemiology and Public Health, Yale Cancer Center, Yale University School of Medicine, 60 College Street, New Haven, CT 06520-8034, USA.
authors.forename: Lingeng
authors.initials: L
authors.lastname: Lu
authors.forename: Dionyssios
authors.initials: D
authors.lastname: Katsaros
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Aaron
authors.initials: A
authors.lastname: Hoffman
authors.forename: Scarampi
authors.initials: S
authors.lastname: Luca
authors.forename: Canuto Emilie
authors.initials: CE
authors.lastname: Marion
authors.forename: Lina
authors.initials: L
authors.lastname: Mu
authors.forename: Harvey
authors.initials: H
authors.lastname: Risch
authors.forename: Herbert
authors.initials: H
authors.lastname: Yu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000378:metabolism*; D019175:DNA Methylation; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013002:Somatomedins / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D013002:Somatomedins; C487931:mirnlet7 microRNA, human