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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2009-08, Vol.69 (16), p.6396-6404
• Main Authors: PAJIC, Marina, IYER, Jayasree K, KERSBERGEN, Ariena, VAN DER BURG, Eline, NYGREN, Anders O. H, JONKERS, Jos, BORST, Piet, ROTTENBERG, Sven
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Antibiotics, Antineoplastic - therapeutic use; Antineoplastic agents; ATP Binding Cassette Transporter, Subfamily B - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP-Binding Cassette Sub-Family B Member 4; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Disease Models, Animal; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug Resistance, Neoplasm - genetics; Female; Gene Expression Regulation, Neoplastic - physiology; Genes, BRCA1; Genes, p53; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Mice; Mice, Knockout; Pharmacology. Drug treatments; Quinolines - pharmacology; Tumor Burden; Tumors; Up-Regulation - physiology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-0041

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.