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Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors.


Shafee, Norazizah and Smith, Christopher R. and Shuanzeng, Wel and Yoo, Kim and Mills, Gordo B. and Hortobagyi, Gabriel N. and Stanbridge, Eric J. (2008) Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors. Cancer Research, 68 (9). pp. 3243-3250. ISSN 0008-5472


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, CD29hi24med, and these cells are tumorigenic, whereas CD29med24–/lo and CD29med24hi 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 CD29hi24med; 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 CD29hi24med 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.

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Additional Metadata

Item Type: Article
Divisions: Faculty of Biotechnology and Biomolecular Sciences
DOI Number: https://doi.org/10.1158/0008-5472.CAN-07-5480
Publisher: American Association for Cancer Research
Keywords: Breast cancer; Stem cells; Chemoresistance.
Depositing User: Ms. Nida Hidayati Ghazali
Date Deposited: 11 Feb 2014 07:45
Last Modified: 11 Feb 2014 07:45
Altmetrics: http://www.altmetric.com/details.php?domain=psasir.upm.edu.my&doi=10.1158/0008-5472.CAN-07-5480
URI: http://psasir.upm.edu.my/id/eprint/13481
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