Effects on human transcriptome of mutated BRCA1 BRCT domain: A microarray study

BMC Cancer

Research Article

Silvia Pellegrini¹  Erika Melissari¹  Veronica Mariotti¹  Caterina Iofrida¹  Lucia Guidugli²  Chiara Guglielmi³  Maria Adelaide Caligo³ 

[1] Department of Experimental Pathology, Medical Biotechnology, Epidemiology and Infectious Diseases, University of Pisa, 56126, Pisa, Italy;Laboratory of Medicine and Pathology, Mayo Clinic, Rochester, MN, USA;Section of Genetic Oncology Division of Surgical, Molecular and Ultrastructural Pathology, Department of Oncology, University of Pisa and Pisa University Hospital, 56126, Pisa, Italy;

关键词: Gene expression;    Microarray analysis;    Missense mutations;    BRCA1 gene;    DNA damage;    DNA repair;    Genomic instability;    Cell proliferation;    Breast neoplasms;    Apoptosis;   

DOI  :  10.1186/1471-2407-12-207

 received in 2012-01-05, accepted in 2012-05-08,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundBRCA1 (breast cancer 1, early onset) missense mutations have been detected in familial breast and ovarian cancers, but the role of these variants in cancer predisposition is often difficult to ascertain. In this work, the molecular mechanisms affected in human cells by two BRCA1 missense variants, M1775R and A1789T, both located in the second BRCT (BRCA1 C Terminus) domain, have been investigated. Both these variants were isolated from familial breast cancer patients and the study of their effect on yeast cell transcriptome has previously provided interesting clues to their possible role in the pathogenesis of breast cancer.MethodsWe compared by Human Whole Genome Microarrays the expression profiles of HeLa cells transfected with one or the other variant and HeLa cells transfected with BRCA1 wild-type. Microarray data analysis was performed by three comparisons: M1775R versus wild-type (M1775RvsWT-contrast), A1789T versus wild-type (A1789TvsWT-contrast) and the mutated BRCT domain versus wild-type (MutvsWT-contrast), considering the two variants as a single mutation of BRCT domain.Results201 differentially expressed genes were found in M1775RvsWT-contrast, 313 in A1789TvsWT-contrast and 173 in MutvsWT-contrast. Most of these genes mapped in pathways deregulated in cancer, such as cell cycle progression and DNA damage response and repair.ConclusionsOur results represent the first molecular evidence of the pathogenetic role of M1775R, already proposed by functional studies, and give support to a similar role for A1789T that we first hypothesized based on the yeast cell experiments. This is in line with the very recently suggested role of BRCT domain as the main effector of BRCA1 tumor suppressor activity.

【 授权许可】

Unknown   
© Iofrida et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.