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 30UTR. 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 30-UTR. Moreover, HER2 status correlates with high PARP1 and low let-7a in breast cancer clinical specimens.