Let-7 Status Is Crucial for PARP1 Expression in HER2-Overexpressing Breast Tumors.

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. 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. .