Moderate increase in Mdr1a/1b expression causes in vivo resistance to doxorubicin in a mouse model for hereditary breast cancer

Cancer Res. 2009 Aug 15;69(16):6396-404. doi: 10.1158/0008-5472.CAN-09-0041. Epub 2009 Aug 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Antibiotics, Antineoplastic / therapeutic use
  • 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
  • Humans
  • Mice
  • Mice, Knockout
  • Quinolines / pharmacology
  • Tumor Burden
  • Up-Regulation / physiology

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • Antibiotics, Antineoplastic
  • Quinolines
  • Doxorubicin
  • multidrug resistance protein 3
  • tariquidar