Abstract A14: Lack of tumor eradication of chemotherapy-sensitive BRCA1;p53-deficient mouse mammary tumors

Abstract

Abstract Many breast cancers respond to chemotherapy or hormonal therapy, however, the lack of tumor eradication is a central clinical problem preceding the development of drug resistant tumors. We have previously studied responses of mammary tumors generated in the K14cre;Brca1F5-13/F5-13;p53F2-10/F2-10 mouse model for hereditary breast cancer to clinically relevant anti-cancer drugs such as doxorubicin, topotecan, cisplatin and the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (1-4). The BRCA1- and p53-deficient tumors generated in this model are hypersensitive to these drugs and never become resistant to cisplatin due to the large, irreversible deletion in Brca1 (5). We show here that even dose-dense treatment with a maximum tolerable dose of cisplatin does not result in tumor eradication. This is not due to the trivial possibility that the drug-resistant remnants are poorly accessible to drug, since we found a homogeneous distribution of the platinum-DNA adducts throughout the tumor. To explain this result we have addressed the hypothesis that the lack of eradication of drug-sensitive tumors is due to increased in vivo chemotherapy resistance of tumor-initiating cells (TICs). Using the CD24 and CD49f cell surface markers which detect normal mouse mammary stem cells, we have identified TICs in BRCA1- and p53-deficient tumors. In addition to the Lin-/CD24+/CD49f+ subpopulation, we show that a larger population of Lin-/CD24+/CD49f-cells also has tumor-initiating capability in at least two serial orthotopic transplantations, suggesting that these are not more differentiated transit-amplifying cells. However, we did not find an enrichment of TICs in cisplatin-treated tumor remnants. We conclude that in this model the resistance of cisplatin-surviving cells cannot be attributed to special biochemical defense mechanisms of TICs. Instead we will present data supporting the hypothesis that surviving TICs arrest in their cell cycle and ‘hibernate’ until the drug is gone. Using Brca1−/−;p53−/− cell lines derived from the mouse tumors we found that only Brca1−/−;p53−/− cells that were in the G0/G1 phase of the cell cycle 24h after cisplatin treatment were capable of forming new colonies, whereas cells in G2 or M were not. Hence, a p53-independent arrest in G0/G1 appears to underlie the lack of eradication of residual Brca1−/−;p53−/− cells. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A14