Abstract
The contribution of ABC-transporters to resistance in patients has remained controversial. We have tackled this problem in a mammary mouse tumor model. These Brca1−/−, p53−/− tumors arise “spontaneously” and closely resemble human breast cancer in BRCA1+/− carriers (Rottenberg, PNAS 2007;104:12117–22; 2008;105:17079–84). The tumors respond to chemotherapeutic agents used in human breast cancer, but eventually end up being resistant to most drugs.
Resistance to doxorubicin in this tumor model is nearly always due to P-glycoprotein upregulation at the transcriptional level. A 5-fold increase in the low basal level of P-glycoprotein RNA in these tumors is sufficient for complete resistance. These levels of P-glycoprotein are not detectable with standard immunocytochemistry using the C219 Mab (Pajic, Cancer Res 2009;69:6396–404). Crossing in null alleles for Mdr1a/b made the tumors hypersensitive to doxorubicin, docetaxel, and to the PARP inhibitor olaparib. In about half of the mice treated with topotecan, resistance is associated with upregulation of Abcg2 (Bcrp). Tumors in Abcg2−/− mice take longer to become resistant (Zander, Cancer Res 2009 in press). Notwithstanding the complete remissions often obtained with some drugs, we are rarely able to eradicate the tumor. This is not due to the hypothetical unique properties of tumor stem cells. Supported by Dutch Cancer Foundation and EU Framework Program.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):PL6-1
RSS Feeds