title: Let-7 Status Is Crucial for PARP1 Expression in HER2-Overexpressing Breast Tumors.
abstract: HER2+breast tumors have been shown to express elevated levels of PARP1 protein. Yet, the mechanism by which PARP1 is upregulated in HER2+breast cancer is unknown. Here, knockdown of HER2 (ERBB2) in HER2+breast cancer cells resulted in a reduction in PARP1 protein. Conversely, ectopic overexpression of HER2 in a non-HER2-overexpressing cell line resulted in increased PARP1 protein levels. Alterations in HER2 expression had no significant effect on PARP1 transcript levels. Instead, HER2 mRNA status was inversely correlated with let-7a miRNA levels in breast cancer cells. Ectopic expression of let-7a miRNA resulted in downregulation of PARP1 protein, whereas expression of the let-7a anti-miRNA increased PARP1 protein. Furthermore, luciferase assays demonstrate that let-7a regulates PARP1 via its 3'UTR. Importantly, let-7a was significantly lower in human HER2+breast tumors compared with HER2-breast tumors and inversely correlated with PARP1 protein levels. Finally, HER2+breast cancer cells exhibited similar cytotoxicity to ectopic let-7a expression as the PARP inhibitor veliparib (ABT-888). Collectively, these results reveal that increased PARP1 expression in HER2+breast cancers is regulated by the let-7a miRNA, and that let-7a is a potential strategy to suppress PARP1 activity.Implications:This study reports the novel findings that HER2 increases PARP1 protein via suppression of the let-7a miRNA, which regulates the PARP1 3'-UTR. Moreover, HER2 status correlates with high PARP1 and low let-7a in breast cancer clinical specimens.Mol Cancer Res; 15(3); 340-7. ©2016 AACR.
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Monica E
authors.initials: ME
authors.lastname: Wielgos
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Rajani
authors.initials: R
authors.lastname: Rajbhandari
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Tiffiny S
authors.initials: TS
authors.lastname: Cooper
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Shi
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.|Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Susan
authors.initials: S
authors.lastname: Nozell
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama. eyang@uab.edu.|Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.|Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.|Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Yang
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000096:biosynthesis* / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation
chemical_list: D035683:MicroRNAs; D000071137:Poly (ADP-Ribose) Polymerase-1; D018719:Erb-b2 Receptor Tyrosine Kinases; C487931:mirnlet7 microRNA, human; C499320:PARP1 protein, human; C508053:ERBB2 protein, human