BRCA1 5083del19 mutant allele selectively up-regulates periostin expression in vitro and in vivo

The aim of this study was to explore the gene expression pattern produced by the cancer-associated BRCA1 5083del19 founder mutation by using a microarray analysis. Such a mutation, identified in a subset of familial breastcancer patients, involves a deletion at the 3' end of the BRCA1 messenger leading, in the mature protein, to the ablation of the BRCT tandem domain.EXPERIMENTAL DESIGN: We generated HeLa cells stably expressing both exogenouswild-type (HeLa/(wt)BRCA1), used as a control, and 5083del19 BRCA1(HeLa/(5083del19)BRCA1) alleles; gene chips were then used to investigate anychanges in the transcription profile induced by the 5083del19 BRCA1 mutantcompared with controls.RESULTS: Among the genes showing perturbation of their expression, periostin was found to be up-regulated in HeLa/(5083del19)BRCA1 cells to an extent of 72-foldversus HeLa/(pcDNA3.1/empty) and 76-fold versus HeLa/(wt)BRCA1 cells. Thisfinding was validated both in vitro in breast cancer cell lines harboring mutations of BRCA1 and in vivo by immunohistochemistry of breast cancer specimensbearing the 5083del19 BRCA1 mutation as well as by Western blot analysis of sera obtained from patients and healthy carriers of the same mutation.CONCLUSIONS: Our results suggest that periostin overexpression, whose product is released from cells in the extracellular fluids, might be a potential marker for early cancer detection in a specific subset of hereditary breast carcinomas triggered by cancer-associated BRCA1 mutations that affect the BRCT tandem domain.