Research ArticleBreast Cancer

Breast Cancer–Associated Abraxas Mutation Disrupts Nuclear Localization and DNA Damage Response Functions

Science Translational Medicine  22 Feb 2012:
Vol. 4, Issue 122, pp. 122ra23
DOI: 10.1126/scitranslmed.3003223

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A New Member of the Cancer Susceptibility Club

Before 1990, breast cancer was generally viewed as genetically intractable, a disease that was the result of a complex interplay between multiple genes and environmental factors. The discovery that it is linked to mutations in BRCA1 in certain families transformed this view, and since that time, mutations in several genes involved in BRCA1-related pathways have also been associated with breast cancer susceptibility. Now, Solyom et al. add a new member to this set.

BRCA1 plays a key role in the DNA damage response via its interactions with multiple proteins. One such protein, Abraxas, organizes a large BRCA1-containing complex that is required for this response. Solyom et al. investigated whether mutations in the Abraxas gene might be linked to familial breast cancer, screening patients from 125 Finnish breast cancer families for germline Abraxas mutations. One mutation (R361Q), which affects a conserved residue in a potential nuclear localization signal, was found in patients from three of the families, but not in healthy female controls. Furthermore, R361Q was found to segregate with a cancer phenotype in the two families for which this analysis was possible. Additionally, the researchers showed that the R361Q mutation impairs the nuclear localization of Abraxas in cultured cells. The mutant protein also was not recruited to sites of DNA damage, unlike its wild-type counterpart. Moreover, expression of the R361Q variant caused hypersensitivity to ionizing radiation and reduced BRCA1 localization at sites of DNA damage in several cell lines. These observations suggest that the Abraxas R361Q variant negatively affects the localization of its binding partners at sites where DNA repair is needed.

The work of Solyom et al. establishes Abraxas as a breast cancer susceptibility gene; in time, the R361Q mutation may be added to a list of mutations for which breast cancer–prone families can be tested.