Breast cancer and HRT: genetic susceptibility within th*

乳腺癌和 HRT：遗传易感性*

• 批准号: 7126782
• 负责人: KATHLEEN E MALONE
• 金额: $ 8.45万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7126782
• 关键词: breast neoplasms; cancer risk; carcinogenesis; cell proliferation; clinical research; estrogens; female; gene expression; genetic susceptibility; hormone metabolism; hormone receptor; hormone regulation /control mechanism; hormone related neoplasm /cancer; hormone therapy; human data; human genetic material tag; human old age (65+); neoplasm /cancer genetics; progesterone; progesterone receptors; receptor binding; single nucleotide polymorphism; women' s health

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.

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。联合激素疗法（CHT）是乳腺癌的危险因素，也是绝经后女性外源性黄体酮和雌激素的主要来源。我们假设外源性孕酮可能影响癌发生的一个关键机制是通过孕酮受体 B (PRB) 对细胞产生增殖作用，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。为了检验这一假设，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 基因中的功能性单核苷酸多态性 (SNP) 和 tagSNP 进行基因分型。我们将研究这些基因的变异是否会改变乳腺癌的整体风险，并改变与 CHT 使用相关的乳腺癌风险。之前没有研究使用更全面的 tagSNP 方法来针对参与黄体酮介导途径的基因组合。最近的证据表明，CHT 等激素介导因素的影响因组织学类型和激素受体状态而异。因此，将针对 ER+/PR+ 肿瘤和小叶肿瘤的风险进行子集分析。这项研究以在西雅图都会区进行的两项基于人群的乳腺癌病例对照研究为基础，对 1,299 名患有浸润性乳腺癌的女性和 1,063 名对照组进行了研究。由于之前收集了暴露数据和 DNA 样本，这项研究非常高效。本研究采用综合 tagSNP 和基于单倍型的方法来评估孕酮介导途径中的基因与乳腺癌风险的关系，特别是与 CHT 对乳腺癌的有害影响有关，在基于人群的环境中提供了最佳的结果。以及测试这一假设的前所未有的策略。通过研究外源性黄体酮影响乳腺癌风险的机制，这项研究为增强我们预防乳腺癌、开发新型抗癌疗法和改进风险评估的能力提供了潜力。