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

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):6396-404]

Sensitivity and Acquired Resistance of BRCA1;p53-Deficient Mouse Mammary Tumors to the Topoisomerase I Inhibitor Topotecan

“…If tumors did not respond (volume remaining, ≥50%), treatments were continued after a recovery time of 9 d after the last treatment. Olaparib and tariquidar were applied as reported (10,17). In topotecan-olaparib combination-treated animals ( Fig.…”

“…(Reverse Transcriptase-)Multiplex ligation-dependent probe amplification (MLPA) analyses on tumor DNA or RNA were carried out as before (9,17).…”

Nanoparticle delivery of anticancer drugs overcomes multidrug resistance in breast cancer

“…A large number of drugs used in cancer chemotherapy are substrates of P-gp, including anthracyclines, topoisomerase inhibitors, vinca alkaloids, camptothecin, and taxanes (Sun et al, 2004;Zhou, 2008). Studies have indicated that even a moderate increase in MDR1 expression (as low as 5-fold) were sufficient to cause doxorubicin resistance (Pajic et al, 2009). …”

Genetically Engineered Mouse Models: Closing the Gap between Preclinical Data and Trial Outcomes

“…Similarly, GEMMs have been successfully used to model acquired resistance to chemotherapy and have provided key insights into the underlying mechanisms and cell types involved. For example, a model of BRCA1-related breast cancer was used to show that even subtle alterations in the levels of a drug efflux transporter in tumor cells can confer resistance to doxorubicin (46,47). In addition, Gilbert and Hemann (48) recently used a wellestablished mouse model of Burkitt's lymphoma to show that stromal factors released from thymic endothelial cells can create a chemoresistant niche that fosters lymphoma cell survival following chemotherapy and eventual tumor relapse.…”