title: Downregulation of hPMC2 imparts chemotherapeutic sensitivity to alkylating agents in breast cancer cells.
abstract: Triple negative breast cancer cell lines have been reported to be resistant to the cyotoxic effects of temozolomide (TMZ). We have shown previously that a novel protein, human homolog of Xenopus gene which Prevents Mitotic Catastrophe (hPMC2) has a role in the repair of estrogen-induced abasic sites. Our present study provides evidence that downregulation of hPMC2 in MDA-MB-231 and MDA-MB-468 breast cancer cells treated with temozolomide (TMZ) decreases cell survival. This increased sensitivity to TMZ is associated with an increase in number of apurinic/apyrimidinic (AP) sites in the DNA. We also show that treatment with another alkylating agent, BCNU, results in an increase in AP sites and decrease in cell survival. Quantification of western blot analyses and immunofluorescence experiments reveal that treatment of hPMC2 downregulated cells with TMZ results in an increase in γ-H2AX levels, suggesting an increase in double strand DNA breaks. The enhancement of DNA double strand breaks in TMZ treated cells upon downregulation of hPCM2 is also revealed by the comet assay. Overall, we provide evidence that downregulation of hPMC2 in breast cancer cells increases cytotoxicity of alkylating agents, representing a novel mechanism of treatment for breast cancer. Our data thus has important clinical implications in the management of breast cancer and brings forth potentially new therapeutic strategies.
authors: a Department of Pharmacology; Case Western Reserve University ; Cleveland , OH USA.
authors: Nirmala
authors: N
authors: Krishnamurthy
authors: Lili
authors: L
authors: Liu
authors: Xiahui
authors: X
authors: Xiong
authors: Junran
authors: J
authors: Zhang
authors: Monica M
authors: MM
authors: Montano
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D005092:Exonucleases / Q000235:genetics*; D005260:Female; D006657:Histones / Q000235:genetics; D006801:Humans; D000077204:Temozolomide
chemical_list: D000477:Alkylating Agents; C468783:H2AX protein, human; D006657:Histones; D003606:Dacarbazine; D005092:Exonucleases; C569254:REXO4 protein, human; D000077204:Temozolomide
keywords: AP, Apurinic/Apyrimidinic sites; BCNU, 1,3-bis-(2-chloroethyl)-1-nitrosourea; BER, Base Excision Repair; ERβ, Estrogen Receptor beta; MX, Methoxyamine; ODD, Oxidative DNA damage; TMZ, Temozolomide; abasic site; base excision repair; double strand breaks; temozolomide