BRCA2overexpression in breast cancer

Introduction

Germ-line mutations in the breast cancer susceptibility gene BRCA2 appear to be responsible for around 20% of hereditary breast cancers. Like BRCA1, BRCA2 is not frequently mutated in sporadic breast carcinomas, although high frequencies of loss of heterozygosity (LOH) at these loci point to a role in the pathogenesis of these tumours, possibly by a mechanism other than structural mutation.

Aims

To investigate BRCA2 gene expression in sporadic breast tumours by quantitative reverse transcriptase polymerase chain reaction (RT-PCR).

Comments

The roles of the breast cancer susceptibility genes BRCA1 and BRCA2 in sporadic breast carcinomas are unclear. Only a small percentage of sporadic breast tumours appear to carry somatic mutations in the BRCA2 gene, despite the fact that 30-40% of sporadic breast cancers show LOH at this locus. The idea that there is another critical gene at 13q12-q13 remains plausible, and BRCA2 may be inactivated by a mechanism other than somatic mutation. The data presented here indicate a role for BRCA2 in the pathogenesis of sporadic breast tumours associated with overexpression, although the mechanisms by which this tumour suppressor gene exerts a positive effect on cell proliferation remain to be determined. The thought that up-regulation of BRCA2 may be a protective response, and BRCA2 expression status may have prognostic significance, is deserving of further investigation.

Methods

Primary breast tumours from 127 patients were analysed, and classified by standard clinicopathological and biological factors. BRCA2 mRNA expression was characterised by quantitative reverse transcriptase (RT)-PCR. LOH analysis was also carried out with four polymorphic microsatellite DNA marker loci flanking BRCA2 on chromosome 13q12-q13.

Results

BRCA2 mRNA expression showed wide variation in the tumour samples analysed. Fourteen tumours (11%) showed underexpression, and 25 (20%) showed overexpression. BRCA2 mRNA overexpression correlated significantly with histopathological grade III, and was mainly attributed to nuclear pleomorphism and mitotic index. No other links between BRCA2 expression and clinicopathological and biological factors were found to be statistically significant. No relationship was observed between LOH at 13q12-q13 and BRCA2 mRNA expression.

Discussion

In this series of 127 primary breast cancers, both underexpression and overexpression of BRCA2 mRNA was observed. The overexpression of BRCA2 demonstrated here was linked with histopathological grade III, suggesting a role in the aggressiveness of breast tumours. In particular, BRCA2 overexpression correlated with the extent of genetic changes in tumours (nuclear pleomorphism) and the proliferation rate (mitotic index). This in vivo data is consistent with in vitro results showing an up-regulation of BRCA2 mRNA in rapidly proliferating cells. Disruption of BRCA2 expression was not due to the loss of one allele as determined by LOH experiments, suggesting the possibility of another key tumour suppressor gene at the 13q12-q13 locus that plays an important role in breast cancer.