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BRCA2-deficient sarcomatoid mammary tumors exhibit multidrug resistance

Janneke E Jaspers1, Wendy Sol2, Ariena Kersbergen2

  • 1Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.

Cancer Research
|December 17, 2014
PubMed

Insights

Multidrug resistance in breast cancer is linked to a specific cell type and P-glycoprotein. Inhibiting P-glycoprotein can help overcome this resistance to chemotherapy and PARP inhibitors.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Pan- or multidrug resistance is a major challenge in clinical oncology.
  • BRCA2-associated hereditary breast cancer presents a model for studying drug resistance mechanisms.

Purpose of the Study:

  • To investigate the mechanisms of multidrug resistance in a genetically engineered mouse model of BRCA2-associated hereditary breast cancer.
  • To explore the role of P-glycoprotein and epithelial-mesenchymal transition (EMT)-like phenotypes in drug resistance.

Main Methods:

  • Utilized a genetically engineered mouse model of BRCA2-associated hereditary breast cancer.
  • Assessed drug resistance to various chemotherapies and poly (ADP-ribose) polymerase (PARP) inhibitors.
  • Analyzed gene expression, focusing on the Abcb1b gene encoding P-glycoprotein.
  • Investigated the effect of P-glycoprotein inhibition on tumor response.

Main Results:

  • Multidrug resistance was strongly associated with an EMT-like sarcomatoid phenotype.
  • High expression of the Abcb1b gene, encoding P-glycoprotein, correlated with multidrug resistance.
  • Inhibition of P-glycoprotein partially restored sensitivity to olaparib, docetaxel, and doxorubicin in sarcomatoid tumors.

Conclusions:

  • Multidrug resistance is a complex, multifactorial process in oncology.
  • Mouse models are valuable tools for dissecting the mechanisms of drug resistance.
  • Targeting P-glycoprotein may offer a strategy to overcome drug resistance in certain breast cancer subtypes.

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