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Nat Commun. 2019 Jan 23;10(1):397. doi: 10.1038/s41467-019-08301-2.

Comparative oncogenomics identifies combinations of driver genes and drug targets in BRCA1-mutated breast cancer.

Author information

1
Division of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
2
Cancer Genomics Netherlands, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
3
Oncode Institute, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
4
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
5
Transgenic Core Facility, Mouse Clinic for Cancer and Aging (MCCA), The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
6
ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
7
Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
8
Preclinical Intervention Unit, Mouse Clinic for Cancer and Aging (MCCA), The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.
9
Department of Medicine, University of Medicine, Parkville, VIC, 3010, Australia.
10
Parkville Familial Cancer Centre, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, VIC, 3050, Australia.
11
Cancer Genomics Netherlands, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands. l.wessels@nki.nl.
12
Oncode Institute, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands. l.wessels@nki.nl.
13
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands. l.wessels@nki.nl.
14
Division of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands. j.jonkers@nki.nl.
15
Cancer Genomics Netherlands, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands. j.jonkers@nki.nl.
16
Oncode Institute, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands. j.jonkers@nki.nl.

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.

PMID:
30674894
PMCID:
PMC6344487
DOI:
10.1038/s41467-019-08301-2
[Indexed for MEDLINE]
Free PMC Article

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