ATPase copper transporter A, negatively regulated by miR-148a-3p, contributes to cisplatin resistance in breast cancer cells

Clin Transl Med. 2020 Jan;10(1):57-73. doi: 10.1002/ctm2.19. Epub 2020 Apr 7.


Background: Breast cancer is the leading cause of death among women. Cisplatin is an effective drug for breast cancer, but resistance often develops during long term chemotherapy. While the mechanism of chemotherapy resistance is still not fully understood.

Methods: Survival analyses of ATP7A and ATP7B were used to evaluate their effects on the development of Breast invasive carcinoma (BRCA). Immunostaining, flow cytometry, and IC50 assay were utilized to examine the effects of ATP7A-siRNA combined with cisplatin on apoptosis in breast cancer cells. Q-PCR, western blotting, and dual-luciferase assay were employed to confirm ATP7A is a novel target gene of miR-148a-3p.

Results: In this current study, we identified knocking-down ATP7A could enhance cytotoxicity treatment of cisplatin in breast cancer cells. We also demonstrated miR-148a-3p overexpression in BRCA cells increased the sensitivity to cisplatin, and subsequently enhanced DNA damage and apoptosis. Moreover, we found ATP7A is a novel target gene of miR-148a-3p. In brief, our results showed miR-148a could accelerate chemotherapy induced-apoptosis in breast cancer cells by inhibiting ATP7A expression.

Conclusions: Our results highlight that inhibition of ATP7A is a potential strategy for targeting breast cancer resistant to cisplatin, and we provided an interesting method to compare the involvement of various genes in the assessment of cisplatin resistance.

Keywords: ATP7A; breast cancer; chemoresistance; cisplatin; miR-148a-3p.