Breast cancer and HRT: genetic susceptibility within th*

描述(由申请人提供)： 乳腺癌是女性最常见的癌症，主要影响老年女性。联合激素治疗(CHT)是乳腺癌的危险因素，也是绝经后妇女外源性黄体酮和雌激素的主要来源。我们推测，外源性孕酮影响肿瘤发生的一个关键机制是通过孕激素受体B(PRB)对细胞的增殖作用，以及外源性孕酮的差异代谢影响孕酮与受体结合的可用性。为了验证这一假设，我们建议对PGR基因以及以下孕酮代谢基因AKR1C1、AKR1C2、AKR1C3、SRD5A1、SRD5A2和CYP3A4基因的功能性单核苷酸多态(SNPs)和标签SNPs进行基因分型。我们将调查这些基因的变异是否改变了乳腺癌的总体风险，并改变了与CHT使用有关的乳腺癌风险。以前还没有研究使用更全面的tag SNPs方法来针对参与孕激素调节途径的这种基因组合。最近的证据表明，激素介导的因素如CHT的影响因组织类型和激素受体状态的不同而不同。因此，将对ER+/PR+肿瘤和小叶肿瘤的风险进行亚集分析。这项针对1,299名患有浸润性乳腺癌的女性和1,063名对照的研究将在西雅图大都市区进行的两项基于人群的乳腺癌病例对照研究的基础上进行。由于之前收集了暴露数据和DNA样本，这项研究效率很高。这项研究使用了基于标签SNP和单倍型的综合方法，在人群环境中评估孕激素调节途径中的基因与乳腺癌风险，特别是与CHT对乳腺癌的有害影响相关，为检验这一假说提供了一种前所未有的最佳策略。通过研究外源性黄体酮影响乳腺癌风险的机制，这项研究提供了提高我们预防乳腺癌的能力、开发新的抗癌疗法和改善风险评估的潜力。

DESCRIPTION (provided by applicant): Breast cancer is the most common cancer in women and predominantly affects older women. Combined hormone therapy (CHT) is a risk factor for breast cancer and is the dominant source of exogenous progesterone and estrogen for post-menopausal women. We postulate that a key mechanism by which exogenous progesterone may influence carcinogenesis is through its proliferative effect on cells via the progesterone receptor B (PRB) and the differential metabolism of exogenous progesterone affecting the availability of progesterone to bind to the receptor. To test this hypothesis, we propose to genotype functional single nucleotide polymorphisms (SNPs) and tagSNPs in the PGR gene, and the following progesterone metabolizing genes, AKR1C1, AKR1C2, AKR1C3, SRD5A1, SRD5A2, and the CYP3A4 gene. We will investigate whether variation in these genes alters the risk of breast cancer overall and modifies the risk of breast cancer in relation to CHT use. No prior study has targeted this combination of genes involved in the progesterone mediating pathway, using the more comprehensive tagSNPs approach. Recent evidence suggests that the effects of hormone-mediated factors like CHT differ according to histologic type and hormone receptor status. Thus, subset analyses will be performed in relation to the risk of ER+/PR+ tumors and lobular tumors. This study of 1,299 women with invasive breast cancer and 1,063 controls will be conducted on the foundation of two population-based case-control studies of breast cancer conducted in the Seattle metropolitan area. This study is highly efficient due to the previous collection of exposure data and DNA samples. The comprehensive tagSNP and haplotype-based approach employed by this study to evaluate genes in the progesterone mediating pathway for association with breast cancer risk, and particularly in relation to the deleterious effect of CHT on breast cancer, in a population-based setting offers an optimal and unprecedented strategy for testing this hypothesis. By investigating the mechanism by which exogenous progesterone impacts breast cancer risk, this study offers the potential to enhance our abilities to prevent breast cancer, develop novel anti-cancer therapies, and improve risk assessment.