Abstract
Cisplatin is an effective breast cancer drug but resistance often develops over prolonged chemotherapy. Therefore, we performed a candidate approach RNAi screen in combination with cisplatin treatment to identify molecular pathways conferring survival advantages. The screen identified ATP7A as a therapeutic target. ATP7A is a copper ATPase transporter responsible for intercellular movement and sequestering of cisplatin. Pharmaceutical replacement for ATP7A by ammonium tetrathiomolybdate (TM) enhanced cisplatin treatment in breast cancer cells. Allograft and xenograft models in athymic nude mice treated with cisplatin/TM exhibited retarded tumor growth, reduced accumulation of cancer stem cells and decreased cell proliferation as compared to mono-treatment with cisplatin or TM. Cisplatin/TM treatment of cisplatin-resistant tumors reduced ATP7A protein levels, attenuated cisplatin sequestering by ATP7A, increased nuclear availability of cisplatin, and subsequently enhanced DNA damage and apoptosis. Microarray analysis of gene ontology pathways that responded uniquely to cisplatin/TM double treatment depicted changes in cell cycle regulation, specifically in the G1/S transition. These findings offer the potential to combat platinum-resistant tumors and sensitize patients to conventional breast cancer treatment by identifying and targeting the resistant tumors' unique molecular adaptations.
Highlights
Breast cancer affects approximately one in eight women in Western countries
Our RNAi library comprised of siRNA against 55 custom-selected genes (Supplementary Table S1), including genes identified in the common genomic gain regions found in the cisplatin resistant breast cancer cells and associated with poor prognosis in breast cancer, which are located on chromosomes 6p12, 6p21, 11q13, 20q13.2 and several regions of 14q [18,19,20,21]
breast cancer associated gene 1 (BRCA1)-mutant breast cancers respond well to platinum agent therapy, which induces DNA crosslinking, as the tumors are deficient in DNA repair; cisplatin resistance often develops [12, 13, 40,41,42,43]
Summary
In the U.S, more than 200,000 new breast cancer cases are diagnosed each year, with about 5% of which is caused by mutations in breast cancer associated gene 1 (BRCA1) and breast cancer associated gene 2 (BRCA2) [1,2,3,4] Platinum drugs such as cisplatin (cis-[PtCl2(NH3)2], cis-diamminedichloroplatinum(II), cDDP), carboplatin and oxaliplatin serve as conventional treatment for breast cancer and other solid tumors [5,6,7]. Previous studies indicate that altered gene expression, DNA copy number changes, and substantial genomic instability contribute to cisplatin resistance [9, 15, 16]. This underscores the need for identification of alternative and ameliorative treatments that re-sensitize cells to platinum agents
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