Tumor levels of the cell cycle regulators
cyclin E and p27 correlate strongly with survival in
breast cancer patients and are specifically regulated by the
ubiquitin ligases hCDC4 and SKP2. This study was to explore whether
genetic susceptibility to
breast cancer is associated with polymorphism of these genes and whether gene-gene and gene-risk factor [i.e. full-term pregnancy (FTP)] interactions are important in determining
cancer risk. A two-stage case-control study based on single-nucleotide polymorphisms was performed. The first study (560 cases and 1122 controls) was to define the contribution of cell cycle and
ubiquitin ligase genes to
cancer susceptibility. The second study (926 cases and 923 controls) was to confirm the association identified in the first stage and to map the variant alleles. Increased
breast cancer risk was associated with both polymorphism of hCDC4 and a joint effect of
cyclin E and hCDC4. These associations were more significant in nulliparous women, and
cancer risk associated with a lower number of FTPs was only seen in women with a higher number of high-risk genotypes, providing support for an effect of gene-risk factor interaction in determining susceptibility. Sequence variants of intron 2 in hCDC4 were found to be the most significant polymorphism and high-stage
estrogen receptor (ER)-negative patients carrying the homozygous variant genotype manifested significantly poorer survival. This study concludes that polymorphism of hCDC4 is a risk factor for
breast cancer development by interacting with either
cyclin E or FTP and may also prove useful in predicting progression of patients with high-stage and ER-negative breast
cancers.