Wild-type genotypes of BRCA1 gene SNPs combined with micro-RNA over-expression in mammary tissue leading to familial breast cancer with an increased risk of distant metastases’ occurrence

• Published in: Medical oncology (Northwood, London, England) Vol. 31; no. 11; p. 255
• Main Authors: Medimegh, Imen, Troudi, Wafa, Stambouli, Nejla, Khodjet-El-Khil, Houssein, Baroudi, Olfa, Ayari, Hajer, Omrane, Ines, Uhrhammer, Nancy, Privat, Maud, Mezlini, Amel, Ayed, Farhat Ben, Romdhane, Khaled Ben, Mader, Sylvie, Bignon, Yve Jean, Elgaaied, Amel Benammar
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01-11-2014; Springer Nature B.V
• Subjects: Adult; Aged; Breast cancer; Breast Neoplasms - diagnosis; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Case-Control Studies; Female; Genetic Predisposition to Disease; Hematology; Humans; Internal Medicine; Medicine; Medicine & Public Health; MicroRNAs - biosynthesis; MicroRNAs - genetics; Middle Aged; Oncology; Original Paper; Pathology; Polymorphism, Single Nucleotide - genetics; Risk Factors; Ubiquitin-Protein Ligases - genetics; Young Adult; Micro-RNA; Familial breast cancer; Metastasis; SNP; Tunisia
• ISSN: 1357-0560; 1559-131X
• DOI: 10.1007/s12032-014-0255-6

Germ line deleterious mutations of
BRCA1
gene are not the unique factor that could inactivate
BRCA1
protein which leads to familial breast cancer onset with distant metastases’ occurrence. The present research explores the role that could be assigned to
BRCA1
SNPs to inactivate
BRCA1
protein and therefore to the occurrence of familial breast cancer with an increased risk of distant metastases’ occurrence. The presence or the absence of
BRCA1
protein was first analyzed by applying the immunohistochemistry technique to the tumors with sporadic and familial breast cancer. Then, a case–control study was conducted including 40 patients with familial breast cancer, 46 ones with sporadic breast cancer and 34 healthy controls based on the genotyping of nine
BRCA1
SNPs (c.442.58delT, c.2082C>T, c.2311T>C, c.2612C>T, c.3113A>G, c.3119G>A, c.3548A>G, c.4308T>C and 4837A>G) via direct sequencing. Finally, the functional role that could be assigned to these SNPs was focused upon. miRbase site was used as a bioinformatics tool to predict potential micro-RNAs (miRs) targeting SNPs that are associated with familial breast cancer according to the results of this research. These predicted miRs were confirmed by Q-PCR analysis and correlated with
BRCA1
protein expression among patients along with potential distant metastases. Clinical outcome showed that distant metastasis concerned 45 % of familial breast cancer patients and 19.5 % with sporadic breast cancer. Analysis of
BRCA1
protein expression revealed a negative staining among 46.6 % of familial breast cancer patients and only 16.6 % within sporadic breast cancer ones. The association of four variants was identified within
BRCA1
gene (c.442.58 delT, c.2311T>C, c.2612C>T and c.4308T>C) to familial breast cancer across their wild genotypes. miR-1179 was selected as potential miR that targets the region of
BRCA1
mRNA containing the c.2311T>C variant within the TT genotype. The expression of miR-1179 was significantly associated with familial breast cancer patients without
BRCA1
deleterious mutations compared to those with sporadic breast cancer according to TT genotype along with
BRCA1
negative staining and according to the occurrence of distant metastases. Combination between TT genotype of c.2311T>C and miR-1179 over-expression could generate a lack of
BRCA1
protein leading to a high risk of familial breast cancer with distant metastases.