性激素代谢在乳腺癌风险评估中的作用和机制研究

Metabolomics is becoming an important emerging discipline at post-genomic era. Previous studies for the biological function of sex hormones and related disease focused on sex hormone receptors and the signal transduction pathways; but neglected sex hormone metabolism and bioactive hormone metabolites. Current conventional sex hormone test only detects three main indicators: estradiol, progesterone, and testosterone mainly in the blood -based detection. This application is developed based on our full range comprehensive sex hormone test (CSHT) to study the metabolism of sex hormones and the roles of different bioactive hormone metabolites on early diagnosis and development of breast cancer. CSHT, using dried urine paper script, is based on metabolomics analysis techniques to detect estrogen, progesterone and testosterone, and their different metabolites. Based on our previous preliminary study, we hypothesize that although there is no significant difference in total level of estrogen in pre-menopausal breast cancer patients vs. age-matched normal healthy women, sex hormone metabolic pathways and related metabolites in breast cancer patients and healthy women are significantly different; especially 4-hydroxy estrogen metabolites are genotoxic, which may be one of the key factors in early development of breast cancer. This study, from the perspective of sex hormone metabolism, will confirm the importance and feasibility of CSHT and using 4-hydroxy estrogen metabolites as a new biomarker for early breast cancer risk assessment.

代谢组学是后基因组时代兴起的一门新兴学科。以往对于性激素的研究着眼于激素受体本身及下游的信号传导，而对于性激素本身的代谢关注较少。常规的性激素检测只停留在血液中雌二醇、孕酮、睾酮这三个主要性激素指标上。本课题的申请是基于我们开发的性激素的全方位代谢组学检测来研究性激素代谢产物,特别是雌激素代谢产物，对乳腺癌的早期临床预测和干预。以干燥尿液（代谢）试纸为载体，检测雌激素、孕激素和雄激素,及其代谢产物的含量和比例。基于我们初步研究，本课题要验证的假说：虽然对比更年期前乳腺癌患者和同龄正常女性总体雌激素没有明显差别,性激素代谢途径和相关的代谢产物在乳腺癌患者和正常女性中有明显的差异；特别是雌激素4-羟基代谢产物具有基因毒性，可能是导致乳腺癌关键因素之一。本课题将从性激素代谢异常的角度，证实全方位代谢组学检测和雌激素代谢产物作为乳腺癌早期预测及评估手段的重要性和可行性并研究其作用机制。

代谢组学是后基因组时代兴起的一门新兴学科。以往对于性激素的研究着眼于激素受体本身及下游的信号传导，而对于性激素本身的代谢关注较少。常规的性激素检测只停留在血液中雌二醇、孕酮、睾酮这三个主要性激素指标上。本课题的申请是基于我们开发的性激素的全方位代谢组学检测来研究性激素代谢产物,特别是雌激素代谢产物，对乳腺癌的早期临床预测和干预。以干燥尿液（代谢）试纸为载体，检测雌激素、孕激素和雄激素及其代谢产物的含量和比例。虽然对比更年期前乳腺癌患者和同龄正常女性总体雌激素没有明显差别，但性激素代谢途径和相关的代谢产物在乳腺癌患者和正常女性中有明显的差异；特别是雌激素4-羟基代谢产物具有基因毒性，可能是导致乳腺癌关键因素之一。通过项目研究我们发现：在绝经前乳腺癌患者尿液中，4羟基雌激素代谢产物明显增加，该代谢产物增加与乳腺癌发病风险有明显关联。4羟基雌激素代谢产物与雌激素的比值可以作为预测乳腺癌风险的指标。在机理方面，我们认为，一方面，四羟基代谢产物可以激活较强的雌激素活性，增强雌激素功能。另一方面，四羟基雌激素代谢产物可以破坏有丝分裂监测点，从而诱导雌激素敏感细胞恶性转化。