Metaplastic breast carcinoma (MBC) is a rare subset of triple-negative breast cancer characterized by a mesenchymal-like phenotype and poor clinical outcome. As BRCA1 deficiency sensitizes tumours to poly(ADP-ribose) polymerase (PARP) inhibitors and most MBCs harbour mutations in BRCA1, Jos Jonkers and colleagues wondered whether MBC could be effectively targeted with PARP inhibitors. The authors generated a genetically engineered mouse model of Brca1-deficient MBC by inducing epithelial–mesenchymal transition by overexpressing the Met oncogene in a previously established mouse model of BRCA1-mutated breast cancer. Mouse MBC showed intrinsic resistance to the PARP inhibitor olaparib owing to overexpression of the drug efflux transporter P-glycoprotein (Pgp). However, using another PARP inhibitor that has low affinity for Pgp (AZD2461) rendered the tumours sensitive to PARP inhibition.
References
Henneman, L. et al. Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer. Proc. Natl Acad. Sci. USA 112, 8409–8414 (2015)
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Villanueva, M. A mouse model for metaplastic breast carcinoma. Nat Rev Cancer 15, 456 (2015). https://doi.org/10.1038/nrc3998
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DOI: https://doi.org/10.1038/nrc3998
