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Polymorphisms in ER- Gene Interact with Estrogen Receptor Status in Breast Cancer Survival

¹ Division of General Internal Medicine, Department of Medicine, Center for Health Services Research, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; and ² Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China

Requests for reprints: Xiao-Ou Shu, Center for Health Service Research, Vanderbilt University, Medical Center East, Suite 6000, Nashville, TN 37232-8300. Phone: 615-936-0713; Fax: 615-936-1269; E-mail: Xiao-Ou.Shu{at}venderbilt.edu.

Purpose: The effects of estrogens are mediated primarily through estrogen receptor (ER) in breast tissue, and polymorphisms in the ER genes may alter the functions of these receptors. Polymorphisms in the ER- gene have been reported to be associated with breast cancer risk. However, to our knowledge, no study has been published on the relation between ER- gene polymorphisms and breast cancer survival.

Experimental Design: To determine whether three common polymorphisms in the ER- gene, PvuII, XbaI, and GT dinucleotide repeats are associated with breast cancer survival, we evaluated data from a cohort of 1,069 breast cancer patients who participated in the Shanghai Breast Cancer Study between 1996 and 1998. The median follow-up time for this cohort of women was 5.2 years.

Results: No overall association was observed between ER gene polymorphisms and breast cancer survival. The genotype associations, however, were modified by ER status in breast cancer tissues. Comparing those with the PP genotype to the pp genotype of the PvuII polymorphism, the hazard ratios (HR) of dying were 3.30 [95% confidence interval (95% CI), 1.42-7.69] and 0.54 (95% CI, 0.24-1.23), respectively, for participants with ER-negative breast cancer and ER-positive breast cancer. Similarly, compared with those with no (GT)₂₃ alleles, carrying one or two (GT)₂₃ alleles of the GT repeat polymorphism was related to a HR of 1.48 (95% CI, 0.77-2.87) for ER-negative breast cancer and a HR of 0.25 (95% CI, 0.09-0.69) for ER-positive cancer. The effect of ER on breast cancer survival was also modified by genotypes of ER- gene. Tests for multiplicative interaction were highly significant.

Conclusions: These data suggest that the ER- gene polymorphisms and ER status may have an interactive effect on breast cancer survival.

Key Words: breast cancer • estrogen • progesterone • receptor • polymorphisms • survival

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