Sporadic breast cancer in young women : a microarray investigation

The aim of this thesis was to test the hypothesis that sporadic breast cancers in young women arise because of a profile of genetic alterations specific to that age group. Previous studies by our research group had identified a higher frequency of Loss of Heterozygosity (LOH) in the BRCA1, BRCA2 and p53 intervals in younger breast cancer cases (55 years); BRCA1 and P53 data had been related to protein expression. Investigations of BRCA2 protein and mRNA expression were inconclusive. A higher frequency of skewed X chromosome inactivation was identified in young women (55 years) with sporadic breast cancer in this study (P = 0.017), which might suggest the involvement of an X linked gene in the genesis of these tumours. Although it was not possible to relate cDNA expression levels to genomic copy number changes for individual tumours, the analysis of gene expression changes using Affymetrix Gene Chips identified a number of novel gene targets showing elevated expression in young breast cancers when compared to normal breast organoids. Several statistically significant candidate genes were investigated, and gene expression changes confirmed by qRT-PCR and for RBBP4 by immunohistochemistry. Of the significant gene targets that were ranked by SAM analysis DDB2 and RARRES3 are the most noteworthy. Statistically significant differences in the level of expression of these two genes might suggest that they are novel markers of young breast cancers, meriting investigation in a larger series of cases.