title: Differential chemotherapeutic sensitivity for breast tumors with "BRCAness": a review.
abstract: BRCA1 or BRCA2 mutations predispose to cancer development, primarily through their loss of role in the repair of DNA double-strand breaks. They play a key role in homologous recombination repair, which is a conservative, error-free DNA repair mechanism. When mutated, other alternative, error-prone mechanisms for DNA repair take over, leading to genomic instability. Somatic mutations are rare in sporadic breast tumors, but expression of BRCA1 and BRCA2 genes can be downregulated in other mechanistic ways. These tumors have similar features in terms of their phenotypic and genotypic profiles, which are normally regulated by these genes, and mutations lead to defective DNA repair capacity, called "BRCAness." Attempts have been made to exploit this differentially expressed feature between tumors and normal tissues by treatment with DNA-damaging chemotherapy agents. Cells with this functional BRCA deficiency should be selectively susceptible to DNA-damaging drugs. Preclinical and early clinical (primarily retrospective) evidence supports this approach. In contrast, there is emerging evidence of relative resistance of tumors containing BRCA1 or BRCA2 mutations (or BRCAness) to taxanes. In this review, we summarize the data supporting differential chemotherapeutic sensitivity on the basis of defective DNA repair. If confirmed with available, clinically applicable techniques, this differential chemosensitivity could lead to treatment choices in breast cancer that have a more individualized biologic basis.
authors.affiliation: University of Arizona Cancer Center, Tucson, Arizona 85724, USA. pchalasani@uacc.arizona.edu
authors.forename: Pavani
authors.initials: P
authors.lastname: Chalasani
authors.forename: Robert
authors.initials: R
authors.lastname: Livingston
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics; D005260:Female; D042822:Genomic Instability; D005838:Genotype; D059765:Homologous Recombination; D006801:Humans; D009154:Mutation
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human
keywords: BRCA mutations; BRCAness; Breast cancer; Differential chemosensitivity