TY - JOUR
T1 - Let-7 status is crucial for PARP1 expression in HER2-overexpressing breast tumors
AU - Wielgos, Monica E.
AU - Rajbhandari, Rajani
AU - Cooper, Tiffiny S.
AU - Wei, Shi
AU - Nozell, Susan
AU - Yang, Eddy S.
N1 - Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/3
Y1 - 2017/3
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-16-0287-T
DO - 10.1158/1541-7786.MCR-16-0287-T
M3 - Article
C2 - 28031413
AN - SCOPUS:85015922641
SN - 1541-7786
VL - 15
SP - 340
EP - 347
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 3
ER -