BRCA2-deficient sarcomatoid mammary tumors exhibit multi-drug resistance

Pan- or multi-drug 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 multi-drug 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 re-sensitize sarcomatoid tumors to the PARP inhibitor olaparib, docetaxel and doxorubicin. We propose that multi-drug resistance is a multi-factorial process and that mouse models are useful to unravel this.