Lai Joe H, Vesprini Danny, Zhang William, Yaffe Martin J, Pollak Michael, Narod Steven A
Centre for Research in Women's Health, University of Toronto, 8790 Bay Street, Toronto, Ontario, M5G 1N8 Canada.
Cancer Epidemiol Biomarkers Prev. 2004 Apr;13(4):573-82.
Mammographic breast density is a significant risk factor for breast cancer. Women with dense tissue accounting for more than 60-75% of the area of the breast have a 4- to 6-fold increase in their risk of breast cancer, compared to women with little or no breast density. A high circulating level of insulin-like growth factor-I (IGF-I) and low IGF binding protein 3 (IGFBP-3) level have been associated with increased breast density in premenopausal women. Genetic polymorphisms in the IGF1 and IGFBP3 genes may influence breast and serum levels of these growth factors. The aims of this study were to determine whether polymorphic variations in the IGF1 and IGFBP3 genes are associated with breast density, and serum IGF-I and IGFBP-3 levels, and whether serum IGF-I and IGFBP-3 levels are associated with mammographic density.
A total of 441 white women, recruited from Women's College Hospital (Toronto, Ontario), enrolled in this study. Each woman completed a questionnaire, detailing information on age, menstrual history, hormone use, diet, and medical and mammography history. Blood samples were taken for DNA extraction to genotype the subjects for polymorphic variants in the two candidate genes, and for measurement of circulating levels of IGF-I and IGFBP-3. Mammographic films were retrieved from Women's College Hospital and digitized using a laser film scanner. The digitized images were assessed for breast density using a computer-assisted method.
There was a positive association between serum IGFBP-3 levels and the number of A alleles at a previously described polymorphic locus in the promoter region of the IGFBP3 gene among premenopausal women (P = 0.01). There was also a positive trend in the mean percentage of breast density by the number of A alleles of the IGFBP3 gene among premenopausal women (P = 0.0005). Women with two A alleles had a 5-fold increase in the odds of having a percentage of breast density greater or equal to 28%, compared with women with no A allele (P = 0.002). However, there was no association between serum IGF-I and IGFBP-3 levels and breast density among premenopausal women (P > 0.05).
This is the first study to report a strong relationship between a polymorphic gene locus (IGFBP3) and mammographic breast density. However, we could not confirm an association between serum IGF-I levels and breast density among premenopausal women, as demonstrated in previous studies.
乳腺钼靶密度是乳腺癌的一个重要风险因素。与乳腺密度低或无乳腺密度的女性相比，乳腺致密组织占乳房面积60%-75%以上的女性患乳腺癌的风险增加4至6倍。胰岛素样生长因子-I（IGF-I）循环水平高和胰岛素样生长因子结合蛋白3（IGFBP-3）水平低与绝经前女性乳腺密度增加有关。IGF1和IGFBP3基因的基因多态性可能影响这些生长因子的乳腺和血清水平。本研究的目的是确定IGF1和IGFBP3基因的多态性变异是否与乳腺密度、血清IGF-I和IGFBP-3水平相关，以及血清IGF-I和IGFBP-3水平是否与乳腺钼靶密度相关。
从女子学院医院（加拿大多伦多安大略省）招募了441名白人女性参与本研究。每位女性都填写了一份问卷，详细说明了年龄、月经史、激素使用情况、饮食以及医疗和乳腺钼靶检查史。采集血样用于DNA提取，以对受试者的两个候选基因的多态性变异进行基因分型，并测量IGF-I和IGFBP-3的循环水平。从女子学院医院检索乳腺钼靶片，并使用激光胶片扫描仪进行数字化处理。使用计算机辅助方法对数字化图像的乳腺密度进行评估。
在绝经前女性中，血清IGFBP-3水平与IGFBP3基因启动子区域先前描述的一个多态性位点的A等位基因数量之间存在正相关（P = 0.01）。在绝经前女性中，乳腺密度的平均百分比也随着IGFBP3基因A等位基因数量呈上升趋势（P = 0.0005）。与无A等位基因的女性相比，有两个A等位基因的女性乳腺密度百分比大于或等于28%的几率增加了5倍（P = 0.002）。然而，绝经前女性的血清IGF-I和IGFBP-3水平与乳腺密度之间没有关联（P > 0.05）。
这是第一项报告多态性基因位点（IGFBP3）与乳腺钼靶密度之间存在密切关系的研究。然而，正如先前研究所表明的，我们无法证实绝经前女性血清IGF-I水平与乳腺密度之间存在关联。
