Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8409-14. doi: 10.1073/pnas.1500223112. Epub 2015 Jun 22.

Abstract

Metaplastic breast carcinoma (MBC) is a rare histological breast cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in breast cancer 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents and poly(ADP-ribose) polymerase (PARP) inhibitors, we sought to investigate the response of BRCA1-deficient MBCs to the PARP inhibitor olaparib. To this end, we established a genetically engineered mouse model (GEMM) for BRCA1-deficient MBC by introducing the MET proto-oncogene into a BRCA1-associated breast cancer model, using our novel female GEMM ES cell (ESC) pipeline. In contrast to carcinomas, BRCA1-deficient mouse carcinosarcomas resembling MBC show intrinsic resistance to olaparib caused by increased P-glycoprotein (Pgp) drug efflux transporter expression. Indeed, resistance could be circumvented by using another PARP inhibitor, AZD2461, which is a poor Pgp substrate. These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics.

Keywords: BRCA1; PARP; breast cancer; mouse model; resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Animals
  • BRCA1 Protein / deficiency*
  • BRCA1 Protein / genetics
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Carcinosarcoma / drug therapy
  • Carcinosarcoma / genetics
  • Carcinosarcoma / metabolism
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism
  • Metaplasia
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phthalazines / pharmacology*
  • Piperazines / pharmacology*
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Survival Analysis

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • BRCA1 Protein
  • Enzyme Inhibitors
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases
  • olaparib