title: Induction of acquired resistance to antiestrogen by reversible mitochondrial DNA depletion in breast cancer cell line.
abstract: Although the net benefits of tamoxifen in adjuvant breast cancer therapy have been proven, the recurrence of the cancer in an aggressive and hormone independent form has been highly problematic. We previously demonstrated the important role mitochondrial DNA (mtDNA) plays in hormone-independence in prostate cancer. Here, the role of mtDNA in breast cancer progression was investigated. We established hydroxytamoxifen (4-OHT) resistant HTRMCF by growing MCF-7, human breast adenocarcinoma cells, in the presence of 4-OHT. HTRMCF was cross-resistant to 4-OHT and ICI182,780 concurrent with the depletion of mtDNA. To further investigate the role of mtDNA depletion, MCF-7 was depleted of mtDNA by treatment with ethidium bromide. MCF Rho 0 was resistant to both 4-OHT and ICI182,780. Furthermore, cybrid (MCFcyb) prepared by fusion MCF Rho 0 with platelet to transfer mtDNA showed susceptibility to antiestrogen. Surprisingly, after withdrawal of 4-OHT for 8 weeks, HTRMCF and their clones became susceptible to both drugs concurrent with a recovery of mtDNA. Herein, our results substantiated the first evidence that the depletion of mtDNA induced by hormone therapy triggers a shift to acquired resistance to hormone therapy in breast cancer. In addition, we showed that mtDNA depletion can be reversed, rendering the cancer cells susceptible to antiestrogen. The fact that the hormone independent phenotype can be reversed should be a step toward more effective treatments for estrogen-responsive breast cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205-7199, USA.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Naito
authors.forename: Jaime
authors.initials: J
authors.lastname: Carcel-Trullols
authors.forename: Cheng-hui
authors.initials: CH
authors.lastname: Xie
authors.forename: Teresa T
authors.initials: TT
authors.lastname: Evans
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Mizumachi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Higuchi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D015139:Blotting, Southern; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004272:DNA, Mitochondrial / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D004996:Ethidium / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D000077267:Fulvestrant; D006801:Humans; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004272:DNA, Mitochondrial; D004273:DNA, Neoplasm; D020847:Estrogen Receptor Modulators; D013629:Tamoxifen; C016601:afimoxifene; D000077267:Fulvestrant; D004958:Estradiol; D004996:Ethidium