© iStockphoto.com/Catherine Yeulet
For women, estrogen is a good thing when everything is working in balance. The hormone promotes the development of female sexual characteristics, such as breasts, stimulates the thickening of the endometrium (the inner lining of the uterus) and regulates many other aspects of the body, such as menstruation and bone growth. However, many studies have shown that when a woman is exposed to too much estrogen, her risk of developing breast and endometrial cancer increases.
To keep estrogen at optimum levels, the body has devised a network of enzymes — encoded by different genes — for regulating estrogen metabolism. Many scientists believe that genetic variations or single nucleotide polymorphisms (SNPs) on certain genes involved in estrogen metabolism may increase breast and endometrial cancer risk. Despite numerous studies, however, scientists have yet to find a metabolic gene or SNP that has a major impact on the development of these hormone-related cancers.
Jianjun Liu at the A*STAR Genome Institute of Singapore and co-workers suspect that breast and endometrial cancer risk may be influenced not by a single metabolic gene or SNP but by ‘weak’ SNPs on several metabolic genes. They have performed a candidate gene-based association study of the metabolic genes in European populations and identified multiple SNPs that work together to increase breast and endometrial cancer risk.
The researchers invited 1,596 breast cancer patients, 719 endometrial cancer patients and 1,730 healthy individuals from Sweden to participate in an initial ‘discovery’ screening. They interrogated 239 SNPs on 35 metabolic genes using traditional methods, but could not identify any significant association with breast or endometrial cancer. However, when they took the cumulative effect of SNPs into consideration, they found a strong association with SNPs on genes involved in androgen–estrogen conversion.
To confirm their results, the researchers invited another 2,245 breast cancer patients and 1,287 healthy individuals from Finland to participate in a second ‘validation’ screening. They interrogated 120 SNPs on genes involved in androgen–estrogen conversion and found a strong association as before. They also found through statistical analysis that CYP19A1 and UGT2B4 are two major metabolic genes associated with breast and endometrial cancer. Interestingly, CYP19A1 is a gene responsible for encoding aromatase, an enzyme responsible for catalyzing the final step in androgen–estrogen conversion — an aromatase inhibitor is currently used for treating hormone-related breast cancer.
The findings demonstrate that seemingly insignificant SNPs, when added up, can have a cumulative effect that can promote certain hormone-related cancers. The knowledge gained through the study could help in the development of better measures for the prevention and treatment of breast and endometrial cancers.
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore.
