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Synergistic Effects of STK15 Gene Polymorphisms and Endogenous Estrogen Exposure in the Risk of Breast Cancer

¹ Department of Medicine, Division of Internal Medicine, Vanderbilt Center for Health Services Research, Vanderbilt-Ingram Cancer Center, Vanderbilt School of Medicine, Veterans Affairs Tennessee Valley Geriatric Research, Education, and Clinical Center, Nashville, Tennessee; ² Department of Epidemiology, Shanghai Cancer Institute, Shanghai, People's Republic of China; and ³ UCSF Comprehensive Cancer Center, Cancer Research Institute, San Francisco, California

Requests for reprints: Wei Zheng, Vanderbilt Center for Health Services Research, 1215 21st Avenue South, Medical Center East, Suite 6000, Nashville, TN 37232-8300. Phone: 615-936-0682; Fax: 615-936-1269. E-mail: wei.zheng{at}vanderbilt.edu

STK15 is a member of a family of serine/threonine kinases that act as key regulators of chromosome segregation and cytokinesis. Over expression of the STK15 gene leads to centrosome amplification, chromosomal instability, aneuploidy, and transformation. It has been reported that the 91T A (Phe Ile at codon 31) polymorphism in the STK15 gene affects the function of this gene. We hypothesized that this polymorphism may interact with endogenous estrogen exposure in the risk of breast cancer and evaluated this hypothesis in a population-based, case-control study conducted among Chinese women in Shanghai. Genotyping assays were completed for 1,102 incident cases and 1,186 community controls. Participation and blood donation rates were over 90% and 80%, respectively. Elevated risks of breast cancer were found to be associated with the Phe/Ile [odds ratio (OR), 1.3; 95% confidence interval (CI), 1.0-1.7] and Ile/Ile (OR, 1.2; 95% CI, 0.9-1.6) genotypes at codon 31 of the STK15 gene, although the ORs were not statistically significant. The risk associated with this polymorphism was modified by factors related to endogenous estrogen exposure, such as high body mass index (BMI), high waist-to-hip ratio, long duration of lifetime menstruation, or long duration of menstruation before first live birth. In particular, a statistically significant interaction was found between BMI and the STK15 Phe³¹Ile polymorphism (P = 0.02) and a positive association with breast cancer risk for the Ile allele was found only among overweight (BMI 25 kg/m²) women with adjusted ORs (95% CIs) of 3.3 (1.4-7.7) and 4.1 (1.7-9.8) associated with the Phe/Ile and Ile/Ile genotypes (Pfor trend <0.01), respectively. The findings from this study are consistent with the evidence from invitro and in vivo experiments, implicating an etiologic role of the STK15 gene in human breast cancer, and provide evidence for the modifying effects of genetic background on human cancer risk.

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