Synergistic chemosensitivity of triple-negative breast cancer cell lines to poly(ADP-Ribose) polymerase inhibition, gemcitabine, and cisplatin.
The basal-like subtype of breast cancer is characterized by a triple-negative (TN) phenotype (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2/neu negative). TN breast cancers share similar gene expression profiles and DNA repair deficiencies with BRCA1-associated breast cancers. BRCA1-mutant cells exhibit sensitivity to gemcitabine, cisplatin, and poly(ADP-ribose) polymerase (PARP) inhibition; therefore, we hypothesized that TN cancer cells may also exhibit sensitivity to these drugs. In this study, we report that TN breast cancer cells are more sensitive to these drugs compared with non-TN breast cancer cells. Moreover, combination treatments indicated that PARP inhibition by the small-molecule inhibitor PJ34 or siRNA knockdown synergized with gemcitabine and cisplatin in TN cells but not in luminal cancer cells. TN cells exhibited reduced repair of UV-induced cyclobutane pyrimidine dimers after PARP inhibition, suggesting that the synergistic effect of PJ34 and gemcitabine or cisplatin reflected inefficient nucleotide excision repair. Mechanistic investigations revealed that in TN cells, PJ34 reduced the levels of ΔNp63α with a concurrent increase in p73 and its downstream target p21. Thus, the sensitivity to combination treatment seemed to be mediated by sustained DNA damage and inefficient DNA repair triggering p63/p73-mediated apoptosis. Our results suggest a novel therapeutic strategy to treat women with TN breast cancer, an aggressive disease that presently lacks effective treatment options.
Hastak
Kedar
K
Division of Oncology, Stanford University School of Medicine, Stanford, California, USA.
Alli
Elizabeth
E
Ford
James M
JM
D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use*; D003114:Colony-Forming Units Assay; D004260:DNA Repair / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D051135:Rad51 Recombinase / Q000378:metabolism; D000093542:Gemcitabine
D000970:Antineoplastic Agents; C468783:H2AX protein, human; D006657:Histones; D003841:Deoxycytidine; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D002945:Cisplatin; D000093542:Gemcitabine
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