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

Stefano Annunziato1,2,3, Julian R de Ruiter1,2,3,4, Linda Henneman1,5

  • 1Division of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.

Nature Communications
|January 25, 2019
PubMed

Insights

Researchers developed new mouse models to study BRCA1-mutated breast cancer, identifying Myc, Met, Pten, and Rb1 as drivers. They also found MCL1 as a collaborating driver, suggesting a combination therapy with PARP inhibitors for better patient outcomes.

Area of Science:

  • Oncology
  • Genetics
  • Cancer Biology

Background:

  • BRCA1-mutated breast cancer is driven by DNA copy-number alterations (CNAs) with numerous candidate driver genes.
  • Validating these drivers necessitates high-throughput in vivo methods for gene function perturbation.

Purpose of the Study:

  • To develop and utilize genetically engineered mouse models (GEMMs) for rapid functional validation of driver genes in BRCA1-deficient breast cancer.
  • To identify novel collaborating drivers and therapeutic targets in this cancer subtype.

Main Methods:

  • Development of GEMMs for BRCA1-deficient breast cancer.
  • Introduction of putative drivers via embryonic stem cell retargeting, lentiviral somatic overexpression, and CRISPR/Cas9 gene disruption.
  • Comparative oncogenomics analysis and iterative mouse modeling.

Main Results:

  • Validated Myc, Met, Pten, and Rb1 as bona fide drivers in BRCA1-associated mammary tumorigenesis.
  • Demonstrated that MYC overexpression significantly alters the CNA landscape in BRCA1-deficient tumors.
  • Identified MCL1 as a collaborating driver and showed MCL1 inhibition enhances PARP inhibitor (PARPi) efficacy in vivo.

Conclusions:

  • Novel GEMMs enable efficient validation of driver genes in BRCA1-mutated breast cancer.
  • MYC and MCL1 are key players in BRCA1-deficient mammary tumorigenesis.
  • Combination therapy of MCL1 inhibition with PARPi shows therapeutic promise for patients with BRCA1-mutated cancer refractory to PARPi monotherapy.

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