Lin28 regulates HER2 and promotes malignancy through multiple mechanisms.
The RNA binding protein Lin28 and its paralog Lin28B are associated with advanced human malignancies. Blocking the biogenesis of let-7 miRNA, a tumor suppressor, by Lin28/Lin28B has been thought to underlie their roles in cancer. Here we report that the mRNA for the human epidermal growth factor receptor 2 (HER2), a HER-family receptor tyrosine kinase known to play a critical role in cell proliferation and survival and also a major therapeutic target in breast cancer, is among several targets of Lin28 regulation. We show that Lin28 stimulates HER2 expression at the posttranscriptional level, and that enforced Lin28 expression promotes cancer cell growth via multiple mechanisms. Consistent with its pleiotropic role in regulating gene expression, Lin28 overexpression in primary breast tumors is a powerful predictor of poor prognosis, representing the first report on the impact of Lin28 expression on clinical outcome in human cancer. While revealing another layer of regulation of HER2 expression in addition to gene amplification, our studies also suggest novel mechanistic insights linking Lin28 expression to disease outcome and imply that targeting multiple pathways is a common mechanistic theme of Lin28-mediated regulation in cancer.
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA.
Chen
C
Feng
Veronique
V
Neumeister
Wei
W
Ma
Jie
J
Xu
Lingeng
L
Lu
Jennifer
J
Bordeaux
Nita J
NJ
Maihle
David L
DL
Rimm
Yingqun
Y
Huang
D000328:Adult; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015331:Cohort Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis
D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C000715187:Lin28A protein, human; C508053:ERBB2 protein, human