Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors.
The majority of BRCA1-associated breast cancers are basal cell-like, which is associated with a poor outcome. Using a spontaneous mouse mammary tumor model, we show that platinum compounds, which generate DNA breaks during the repair process, are more effective than doxorubicin in Brca1/p53-mutated tumors. At 0.5 mg/kg of daily cisplatin treatment, 80% primary tumors (n = 8) show complete pathologic response. At greater dosages, 100% show complete response (n = 19). However, after 2 to 3 months of complete remission following platinum treatment, tumors relapse and become refractory to successive rounds of treatment. Approximately 3.8% to 8.0% (mean, 5.9%) of tumor cells express the normal mammary stem cell markers, CD29(hi)24(med), and these cells are tumorigenic, whereas CD29(med)24(-/lo) and CD29(med)24(hi) cells have diminished tumorigenicity or are nontumorigenic, respectively. In partially platinum-responsive primary transplants, 6.6% to 11.0% (mean, 8.8%) tumor cells are CD29(hi)24(med); these populations significantly increase to 16.5% to 29.2% (mean, 22.8%; P < 0.05) in platinum-refractory secondary tumor transplants. Further, refractory tumor cells have greater colony-forming ability than the primary transplant-derived cells in the presence of cisplatin. Expression of a normal stem cell marker, Nanog, is decreased in the CD29(hi)24(med) populations in the secondary transplants. Top2A expression is also down-regulated in secondary drug-resistant tumor populations and, in one case, was accompanied by genomic deletion of Top2A. These studies identify distinct cancer cell populations for therapeutic targeting in breast cancer and implicate clonal evolution and expansion of cancer stem-like cells as a potential cause of chemoresistance.
Shafee
Norazizah
N
Department of Microbiology and Molecular Genetics, College of Medicine, University of California, Irvine, CA 92697, USA.
Smith
Christopher R
CR
Wei
Shuanzeng
S
Kim
Yoon
Y
Mills
Gordon B
GB
Hortobagyi
Gabriel N
GN
Stanbridge
Eric J
EJ
Lee
Eva Y-H P
EY
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D002945:Cisplatin / Q000627:therapeutic use*; D004250:DNA Topoisomerases, Type II / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D016158:Genes, p53; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology*; D000075223:Poly-ADP-Ribose Binding Proteins; D014410:Tumor Stem Cell Assay
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D004250:DNA Topoisomerases, Type II; C000618812:Top2a protein, mouse; D002945:Cisplatin