| First Author | Pajic M | Year | 2009 |
| Journal | Cancer Res | Volume | 69 |
| Issue | 16 | Pages | 6396-404 |
| PubMed ID | 19654309 | Mgi Jnum | J:151760 |
| Mgi Id | MGI:4355247 | Doi | 10.1158/0008-5472.CAN-09-0041 |
| Citation | Pajic M, et al. (2009) Moderate increase in Mdr1a/1b expression causes in vivo resistance to doxorubicin in a mouse model for hereditary breast cancer. Cancer Res 69(16):6396-404 |
| abstractText | We have found previously that acquired doxorubicin resistance in a genetically engineered mouse model for BRCA1-related breast cancer was associated with increased expression of the mouse multidrug resistance (Mdr1) genes, which encode the drug efflux transporter ATP-binding cassette B1/P-glycoprotein (P-gp). Here, we show that even moderate increases of Mdr1 expression (as low as 5-fold) are sufficient to cause doxorubicin resistance. These moderately elevated tumor P-gp levels are below those found in some normal tissues, such as the gut. The resistant phenotype could be completely reversed by the third-generation P-gp inhibitor tariquidar, which provides a useful strategy to circumvent this type of acquired doxorubicin resistance. The presence of MDR1A in drug-resistant tumors with a moderate increase in Mdr1a transcripts could be shown with a newly generated chicken antibody against a mouse P-gp peptide. Our data show the usefulness of realistic preclinical models to characterize levels of Mdr1 gene expression that are sufficient to cause resistance. |
