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A major contributing factor to the development of breast cancer is decreased functional expression of breast cancer susceptibility gene 1, BRCA1. Another key contributor to tumorigenesis is hypoxia. Here we show that hypoxia increased the nuclear localization of BRCA1 in MCF-7 and MDA-MB-468 human breast cancer cell lines without changing its steady-state expression level. Nuclear accumulation of BRCA1 was not evident in MCF-12A or HMEC (human mammary epithelial cell) nonmalignant mammary epithelial cells under the same conditions. Hypoxia also increased the cell surface expression of TRAIL on MDA-MB-468 cells. Neutralization of TRAIL precluded the hypoxia-induced accumulation of BRCA1 in the nucleus, whereas exogenously administered TRAIL mimicked the effect. Treatment of MDA-MB-468 cells with TRAIL resulted in a dose- and time-dependent increase in apoptosis. Furthermore, TRAIL-induced apoptosis in HCC1937 cells, which harbor a BRCA1 mutation, increased synergistically when wild-type BRCA1 was reconstituted in the cells, and downregulation of BRCA1 expression in MDA-MB-468 cells reduced the apoptotic response to TRAIL. These data provide a novel link between hypoxia, TRAIL and BRCA1, and suggest that this relationship may be especially relevant to the potential use of TRAIL as a chemotherapeutic agent.