This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-09-0041v1 69/16/6396    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pajic, M. Articles by Rottenberg, S. Search for Related Content PubMed PubMed Citation Articles by Pajic, M. Articles by Rottenberg, S.

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

¹ Division of Molecular Biology and Centre for Biomedical Genetics, The Netherlands Cancer Institute; ² MRC-Holland, Amsterdam, The Netherlands

Request for reprints: Sven Rottenberg, Division of Molecular Biology and Centre for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Phone: 31-205122082; Fax: 31-206691383; E-mail: s.rottenberg{at}nki.nl.

Key Words: doxorubicin • multidrug resistance • P-glycoprotein • breast cancer • BRCA1

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]

This article has been cited by other articles:

				S. A.L. Zander, A. Kersbergen, E. van der Burg, N. de Water, O. van Tellingen, S. Gunnarsdottir, J. E. Jaspers, M. Pajic, A. O.H. Nygren, J. Jonkers, et al. Sensitivity and Acquired Resistance of BRCA1;p53-Deficient Mouse Mammary Tumors to the Topoisomerase I Inhibitor Topotecan Cancer Res., February 15, 2010; 70(4): 1700 - 1710. [Abstract] [Full Text] [PDF]

				C. N. Bennett and J. E. Green Genomic Analyses as a Guide to Target Identification and Preclinical Testing of Mouse Models of Breast Cancer Toxicol Pathol, January 1, 2010; 38(1): 88 - 95. [Abstract] [Full Text] [PDF]