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

Henneman, Linda; van Miltenburg, Martine H; Michalak, Ewa M; Braumuller, Tanya M; Jaspers, Janneke E; Drenth, Anne Paulien; de Korte-Grimmerink, Renske; Gogola, Ewa; Szuhai, Karoly; Schlicker, Andreas; Bin Ali, Rahmen; Pritchard, Colin; Huijbers, Ivo J; Berns, Anton; Rottenberg, Sven; Jonkers, Jos (2015). Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 112(27), pp. 8409-8414. National Academy of Sciences NAS 10.1073/pnas.1500223112

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

05 Veterinary Medicine > Research Foci > Host-Pathogen Interaction
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Animal Pathology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

Rottenberg, Sven

Subjects:

600 Technology > 630 Agriculture

ISSN:

0027-8424

Publisher:

National Academy of Sciences NAS

Language:

English

Submitter:

Barbara Gautschi-Steffen

Date Deposited:

15 Feb 2016 13:47

Last Modified:

30 Sep 2016 15:06

Publisher DOI:

10.1073/pnas.1500223112

PubMed ID:

26100884

Uncontrolled Keywords:

BRCA1; PARP; breast cancer; mouse model; resistance

BORIS DOI:

10.7892/boris.75558

URI:

https://boris.unibe.ch/id/eprint/75558

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