Data from Moderate Increase in <i>Mdr1a/1b</i> Expression Causes <i>In vivo</i> Resistance to Doxorubicin in a Mouse Model for Hereditary Breast Cancer

Abstract

<div>Abstract<p>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 <i>multidrug resistance</i> (<i>Mdr1</i>) genes, which encode the drug efflux transporter ATP-binding cassette B1/P-glycoprotein (P-gp). Here, we show that even moderate increases of <i>Mdr1</i> 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 <i>Mdr1a</i> 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 <i>Mdr1</i> gene expression that are sufficient to cause resistance. [Cancer Res 2009;69(16):6396–9]</p></div>