Homologous recombination deficiency in breast cancer: Implications for risk, cancer development, and therapy

Rayhaan M.M. Ali, Stuart A. McIntosh*, Kienan I. Savage*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

2 Citations (Scopus)

Abstract

An underlying cause of breast cancers has been largely attributed to defects in the DNA damage response (DDR) pathway. In particular, the homologous recombination (HR) pathway repairs double-stranded breaks (DSBs) in DNA, ultimately protecting the cell from genomic instability and thus preventing the accumulation of transforming mutations. In line with this, mutations in a number of genes encoding HR proteins are a well-studied cause of HR deficiency (HRD), and, at the germline level, can confer risk to breast cancer but also occur somatically, contributing to sporadic breast cancer development, progression and response to therapy. Our understanding of the biological processes involved in HR and how these become compromised during breast cancer development has led to a better understanding of how HRD cells can be targeted with specific DNA damaging agents and/or with synthetic lethal targeting approaches such as PARP inhibition. Additionally, in vitro and preclinical modeling has supported the development of clinical trials to assess targeted therapies such as PARP inhibitors (PARPis), ultimately leading to development of therapies with greater clinical benefit. A number of challenges have been encountered, including resistance to therapy; however, addressing these challenges head-on and continually driving scientific research and clinical trials with innovative therapies will contribute to our ability to target HRD in breast cancers. Ongoing research efforts into HRD in breast cancer development are therefore essential, even in the era of targeted therapies, to provide innovative strategies for improved tumor responses.

Original languageEnglish
Pages (from-to)358-372
JournalGenes Chromosomes and Cancer
Volume60
Issue number5
Early online date09 Dec 2020
DOIs
Publication statusPublished - May 2021

Keywords

  • breast cancer
  • chemotherapy
  • DNA repair
  • homologous recombination
  • PARP inhibitors

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

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