{"doi":"10.1158/0008-5472.c.6497703","title":"Data from Cancer Stem Cells Contribute to Cisplatin Resistance in <i>Brca1/p53</i>–Mediated Mouse Mammary Tumors","abstract":"<div>Abstract<p>The majority of <i>BRCA1</i>-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 <i>Brca1/p53</i>–mutated tumors. At 0.5 mg/kg of daily cisplatin treatment, 80% primary tumors (<i>n</i> = 8) show complete pathologic response. At greater dosages, 100% show complete response (<i>n</i> = 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<sup>hi</sup>24<sup>med</sup>, and these cells are tumorigenic, whereas CD29<sup>med</sup>24<sup>−/lo</sup> and CD29<sup>med</sup>24<sup>hi</sup> 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<sup>hi</sup>24<sup>med</sup>; these populations significantly increase to 16.5% to 29.2% (mean, 22.8%; <i>P</i> < 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, <i>Nanog</i>, is decreased in the CD29<sup>hi</sup>24<sup>med</sup> populations in the secondary transplants. <i>Top2A</i> expression is also down-regulated in secondary drug-resistant tumor populations and, in one case, was accompanied by genomic deletion of <i>Top2A</i>. 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. [Cancer Res 2008;68(9):3243–50]</p></div>","journal":null,"year":2023,"id":404080,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9522,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":850709,"name":"Christopher R. Smith","orcid":"0000-0003-2795-0922","position":1,"is_corresponding":false},{"id":730177,"name":"Shuanzeng Wei","orcid":"0000-0002-0441-6973","position":2,"is_corresponding":false},{"id":599892,"name":"Yoon Kim","orcid":"0000-0001-7257-1679","position":3,"is_corresponding":false},{"id":13817,"name":"Gordon B. Mills","orcid":"0000-0002-0144-9614","position":4,"is_corresponding":false},{"id":299476,"name":"Gabriel N. Hortobágyi","orcid":"0000-0002-4873-4412","position":5,"is_corresponding":false},{"id":533787,"name":"Eric J. Stanbridge","orcid":null,"position":6,"is_corresponding":false},{"id":1181889,"name":"Eva Y-H. P. Lee","orcid":null,"position":7,"is_corresponding":false},{"id":868862,"name":"Norazizah Shafee","orcid":"0000-0002-6877-7612","position":0,"is_corresponding":true}],"reference_count":29,"raw_metadata":null,"created_at":"2026-07-19T01:20:40.264741Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}