BRCA1 is a tumor suppressor gene that is mutated in families with breast and 
ovarian cancer. Several BRCA1 splice variants are found in different tissues, 
but their subcellular localization and functions are poorly understood at the 
moment. We previously described BRCA1 splice variant BRCA1a to induce apoptosis 
and function as a tumor suppressor of triple negative breast, ovarian and 
prostate cancers. In this study we have analyzed the function of BRCA1 isoforms 
(BRCA1a and BRCA1b) and compared them to the wild-type BRCA1 protein using 
several criteria like studying expression in normal and tumor cells by RNase 
protection assays, subcellular localization/fractionation by immunofluorescence 
microscopy and Western blot analysis, transcription regulation of biological 
relevant proteins and growth suppression in breast cancer cells. We are 
demonstrating for the first time that ectopically expressed GFP-tagged BRCA1, 
BRCA1a, and BRCA1b proteins are localized to the mitochondria, repress ELK-1 
transcriptional activity and possess antiproliferative activity on breast cancer 
cells. These results suggest that the exon 9, 10, and 11 sequences (aa 263-1365) 
which contain two nuclear localization signals, p53, Rb, c-Myc, gamma-tubulin, 
Stat, Rad51, Rad50 binding domains, angiopoietin-1 repression domain are not 
absolutely required for mitochondrial localization and growth suppressor 
function of these proteins. Since mitochondrial dysfunction is a hallmark of 
cancer, we can speculate that the mitochondrial localization of BRCA1 proteins 
may be functionally significant in regulating both the mitochondrial DNA damage 
as well as apoptotic activity of BRCA1 proteins and mislocalization causes 
cancer. J. Cell. Physiol. 219: 634-641, 2009. (c) 2009 Wiley-Liss, Inc.