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Supplementary Figures 1-4 from Moderate Increase in Mdr1a/1b Expression Causes In vivo Resistance to Doxorubicin in a Mouse Model for Hereditary Breast Cancer

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posted on 2023-03-30, 18:43 authored by Marina Pajic, Jayasree K. Iyer, Ariena Kersbergen, Eline van der Burg, Anders O.H. Nygren, Jos Jonkers, Piet Borst, Sven Rottenberg
Supplementary Figures 1-4 from Moderate Increase in Mdr1a/1b Expression Causes In vivo Resistance to Doxorubicin in a Mouse Model for Hereditary Breast Cancer

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ARTICLE ABSTRACT

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. [Cancer Res 2009;69(16):6396–9]

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    Cancer Research

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    Keywords

    Breast CancerDrug ResistanceClinical drug resistanceNon-transporter-based drug resistanceReversal of drug resistanceTransporter-based drug resistanceOncogenes & Tumor SuppressorsBRCA familyPreclinical Models

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