Phenol sulfotransferases: Hormonal regulation, polymorphism, and age of onset of breast cancer

In recent years, significant effort has been made to identify genes that in fluence breast cancer risk. Because the high-penetrance breast cancer susce ptibility genes BRCA1 acid 2 play a role only in a small fraction of breast cancer cases, understanding the genetic risk of the majority of breast can cers will require the identification and analysis of several lower penetran ce genes. The estrogen-signaling pathway plays a crucial role in the pathop hysiology of breast cancer; therefore, polymorphism in genes involved in th is pathway is likely to influence breast cancer risk. Our detailed analysis of gene expression profiles of estrogen- and il-OH-tamoxifen-treated ZR75- 1 breast cancer cells identified members of the sulfotransferase 1A (SULT1A ) phenol sulfotransferase family as downstream targets of tamoxifen, On the basis of the induction of SULT1A by 4-OH-tamoxifen and the known inherited variability in SULT1A enzymatic activity, we hypothesized that polymorphis m in sulfotransferase genes might influence the risk of breast cancer, Usin g an RFLP that distinguishes an arginine to histidine change in exon 7 of t he SULT1A1 gene, we characterized SULT1A1 genotypes in relation to breast c ancer risk. An analysis of 444 breast cancer patients and 227 controls reve aled no effect of SULT1A1 genotype on the risk of breast cancer (P = 0.69); however, it did appear to influence tbe age of onset among early-onset aff ected patients (P = 0.04), Moreover, individuals with the higher activity S ULT1A1*1 allele were more likely to have other tumors in addition to breast cancer (P = 0.004; odds ratio, 3.02; 95% confidence interval, 1.32, 8.09). The large number of environmental mutagens and carcinogens activated by su lfotransferases and the high frequency of the SULT1A1*1 allele in human pop ulations warrants additional studies to address the role of SULT genes in h uman cancer.