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Phenol Sulfotransferases: Hormonal Regulation, Polymorphism, and Age of Onset of Breast Cancer¹

Departments of Adult Oncology [P. S., H. G., J. E. G., K. P.], and Biostatistics [K. L. L.], Dana-Farber Cancer Institute, Boston, Massachusetts 02115; Brigham and Women’s Hospital [E. R., C. M. K., D. J. I.], Boston, Massachusetts 02115; Center for Cancer Risk Analysis, Massachusetts General Hospital, Charlestown, Massachusetts 02129 [D. W. B., D. A. H.]; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114 [S. M. N.]; Harvard Medical School, Boston, Massachusetts 02115 [P. S., D. W. B., H. G., S. M. N., E. R., C. M. K., D. J. I., J. E. G., D. A. H., K. P.]; Harvard School of Public Health, Boston, Massachusetts 02115 [K. L. L.]; and Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710 [J. R. M.]

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.

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