In recent years, significant effort has been made to identify genes that influence
breast cancer risk. Because the high-penetrance
breast cancer susceptibility genes BRCA1 and 2 play a role only in a small fraction of
breast cancer cases, understanding the genetic risk of the majority of breast
cancers will require the identification and analysis of several lower penetrance genes. The
estrogen-signaling pathway plays a crucial role in the pathophysiology of
breast cancer; therefore, polymorphism in genes involved in this pathway is likely to influence
breast cancer risk. Our detailed analysis of gene expression profiles of
estrogen- and 4-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 polymorphism in
sulfotransferase genes might influence the risk of
breast cancer. Using an RFLP that distinguishes an
arginine to
histidine change in exon 7 of the SULT1A1 gene, we characterized SULT1A1 genotypes in relation to
breast cancer risk. An analysis of 444
breast cancer patients and 227 controls revealed no effect of SULT1A1 genotype on the risk of
breast cancer (P = 0.69); however, it did appear to influence the age of onset among early-onset affected patients (P = 0.04). Moreover, individuals with the higher activity SULT1A1*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
sulfotransferases and the high frequency of the SULT1A1*1 allele in human populations warrants additional studies to address the role of SULT genes in human
cancer.