Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer
Details
Publication Year 2019-01-23, Volume 10, Issue #1, Page 397
Journal Title
Nature Communications
Publication Type
Journal Article
Abstract
BRCA1-mutated breast cancer is primarily driven by DNA copy-number alterations (CNAs) containing large numbers of candidate driver genes. Validation of these candidates requires novel approaches for high-throughput in vivo perturbation of gene function. Here we develop genetically engineered mouse models (GEMMs) of BRCA1-deficient breast cancer that permit rapid introduction of putative drivers by either retargeting of GEMM-derived embryonic stem cells, lentivirus-mediated somatic overexpression or in situ CRISPR/Cas9-mediated gene disruption. We use these approaches to validate Myc, Met, Pten and Rb1 as bona fide drivers in BRCA1-associated mammary tumorigenesis. Iterative mouse modeling and comparative oncogenomics analysis show that MYC-overexpression strongly reshapes the CNA landscape of BRCA1-deficient mammary tumors and identify MCL1 as a collaborating driver in these tumors. Moreover, MCL1 inhibition potentiates the in vivo efficacy of PARP inhibition (PARPi), underscoring the therapeutic potential of this combination for treatment of BRCA1-mutated cancer patients with poor response to PARPi monotherapy.
Publisher
Springer Nature
WEHI Research Division(s)
Cancer Biology And Stem Cells
PubMed ID
30674894
Open Access at Publisher's Site
https://doi.org/10.1038/s41467-019-08301-2
NHMRC Grants
NHMRC/113133 NHMRC/1078730 NHMRC/1102742
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2019-03-13 08:04:11
Last Modified: 2019-03-13 10:02:01
An error has occurred. This application may no longer respond until reloaded. Reload 🗙