Abstract
Pan- or multidrug resistance is a central problem in clinical oncology. Here, we use a genetically engineered mouse model of BRCA2-associated hereditary breast cancer to study drug resistance to several types of chemotherapy and PARP inhibition. We found that multidrug resistance was strongly associated with an EMT-like sarcomatoid phenotype and high expression of the Abcb1b gene, which encodes the drug efflux transporter P-glycoprotein. Inhibition of P-glycoprotein could partly resensitize sarcomatoid tumors to the PARP inhibitor olaparib, docetaxel, and doxorubicin. We propose that multidrug resistance is a multifactorial process and that mouse models are useful to unravel this.
©2014 American Association for Cancer Research.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ATP Binding Cassette Transporter, Subfamily B / biosynthesis
-
ATP Binding Cassette Transporter, Subfamily B / genetics*
-
Animals
-
Antineoplastic Agents / administration & dosage
-
BRCA2 Protein / deficiency
-
BRCA2 Protein / genetics*
-
Breast Neoplasms / drug therapy
-
Breast Neoplasms / genetics
-
Breast Neoplasms / pathology
-
Doxorubicin / administration & dosage
-
Drug Resistance, Multiple / genetics*
-
Drug Resistance, Neoplasm / genetics
-
Enzyme Inhibitors / administration & dosage
-
Female
-
Gene Expression Regulation, Neoplastic / drug effects
-
Humans
-
Mammary Neoplasms, Animal / drug therapy
-
Mammary Neoplasms, Animal / genetics*
-
Mammary Neoplasms, Animal / pathology
-
Mice
-
Poly(ADP-ribose) Polymerase Inhibitors
Substances
-
ATP Binding Cassette Transporter, Subfamily B
-
Antineoplastic Agents
-
BRCA2 Protein
-
Enzyme Inhibitors
-
Poly(ADP-ribose) Polymerase Inhibitors
-
Doxorubicin
-
Abcb1b protein, mouse