AI Article Synopsis

  • BRCA1 is a key tumor suppressor gene linked to familial breast cancer, particularly aggressive triple-negative types, and has roles in DNA repair and other crucial cellular processes.
  • The study reveals that BRCA1 also functions as a translational regulator, influencing the production of specific proteins that are important for cancer biology.
  • Findings suggest that translational control by BRCA1 could be a new mechanism underlying its tumor-suppressive activity, with the potential to identify ADAT2 as a biomarker for treatment response in patients with BRCA1 deficiencies.

Article Abstract

BRCA1 inactivation is a hallmark of familial breast cancer, often associated with aggressive triple negative breast cancers. BRCA1 is a tumor suppressor with known functions in DNA repair, transcription regulation, cell cycle control, and apoptosis. In the present study, we demonstrate that BRCA1 is also a translational regulator. We previously showed that BRCA1 was implicated in translation regulation. Here, we asked whether translational control could be a novel function of BRCA1 that contributes to its tumor suppressive activity. A combination of RNA-binding protein immunoprecipitation, microarray analysis, and polysome profiling, was used to identify the mRNAs that were specifically deregulated under BRCA1 deficiency. Western blot analysis allowed us to confirm at the protein level the deregulated translation of a subset of mRNAs. A unique and dedicated cohort of patients with documented germ-line BRCA1 pathogenic variant statues was set up, and tissue microarrays with the biopsies of these patients were constructed and analyzed by immunohistochemistry for their content in each candidate protein. Here, we show that BRCA1 translationally regulates a subset of mRNAs with which it associates. These mRNAs code for proteins involved in major programs in cancer. Accordingly, the level of these key proteins is correlated with BRCA1 status in breast cancer cell lines and in patient breast tumors. ADAT2, one of these key proteins, is proposed as a predictive biomarker of efficacy of treatments recently recommended to patients with BRCA1 deficiency. This study proposes that translational control may represent a novel molecular mechanism with potential clinical impact through which BRCA1 is a tumor suppressor.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226996PMC
http://dx.doi.org/10.3390/cells9040941DOI Listing

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