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

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

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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA1 Protein / genetics*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Carcinogenesis / genetics*
  • Cell Transformation, Neoplastic / genetics
  • Collagen Type I / genetics
  • DNA Copy Number Variations / genetics*
  • Embryonic Stem Cells
  • Female
  • Gene Expression Regulation, Neoplastic / genetics*
  • Gene Regulatory Networks
  • HEK293 Cells
  • Humans
  • Mammary Neoplasms, Animal / genetics
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Transcriptome
  • Tumor Suppressor Protein p53 / genetics

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • Collagen Type I
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Tumor Suppressor Protein p53
  • collagen type I, alpha 1 chain