Comparative Oncogenomics Identifies Combinations of Driver Genes and Drug Targets in BRCA1-mutated Breast Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Jan 25

PMID 30674894

Citations 41

Authors

Stefano Annunziato

Julian R de Ruiter

Linda Henneman

Chiara S Brambillasca

Catrin Lutz

Francois Vaillant

Federica Ferrante

Anne Paulien Drenth

Eline van der Burg

Bjorn Siteur

Bas van Gerwen

Roebi de Bruijn

Martine H van Miltenburg

Ivo J Huijbers

Marieke van de Ven

Jane E Visvader

Geoffrey J Lindeman

Lodewyk F A Wessels

Jos Jonkers

Affiliations

Soon will be listed here.

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.

Citing Articles

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Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer.

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