Abraxas Is a Breast Cancer Susceptibility Gene

Germline BRCA1 and BRCA2 mutations are important risk factors for breast cancer but account for no more than 20% of familial breast cancer cases. Several genes that encode DNA repair proteins capable of directly or indirectly interacting with BRCA1 and BRCA2 have also been identified as breast cancer susceptibility genes, suggesting that disruption of multiple nodes of a BRCA1-centered tumor suppressor network can increase breast cancer risk. Solyom and colleagues screened 125 Finnish breast cancer families for mutations in Abraxas (ABRA1), which encodes a protein that interacts with the BRCT domains of BRCA1. A germline variant in which an evolutionarily conserved arginine residue in a putative nuclear localization signal was changed to a glutamine residue (R361Q) was identified in 3 of the 125 breast cancer families and another unselected breast cancer patient (who turned out to have a familial cancer background) but was absent from 868 healthy women who served as control subjects. This Abraxas mutation segregated with the cancer phenotype, and did not co-occur with BRCA1 or BRCA2 mutations. The R361Q mutant still bound BRCA1, but was no longer predominantly localized in the nucleus and was not recruited to irradiation-induced DNA damage foci. Furthermore, Abraxas R361Q expression significantly reduced BRCA1 irradiation-induced foci formation, increased radiosensitivity, disrupted the irradiation-induced G₂ checkpoint, and reduced the efficiency of homology-directed double-strand break repair. Together, these findings implicate Abraxas as a breast cancer susceptibility gene whose mutation disrupts BRCA1 localization to double-strand breaks and DNA repair in a dominant-negative manner.

Solyom S, Aressy B, Pylkäs K, Patterson-Fortin J, Hartikainen JM, Kallioniemi A, et al. Breast cancer-associated Abraxas mutation disrupts nuclear localization and DNA damage response functions. Sci Transl Med 2012;4:122ra23.

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