Biomarkers of Tumor Initiation in Breast Cancer

描述(申请人提供)：虽然美国有相当大比例的女性在有生之年被认为患有乳腺癌的风险很高(Graubard 2010)，但大多数人永远不会患上乳腺癌。被认为是高危女性面临着控制癌症的大多数困难选择。一些患者有资格接受内分泌治疗，如他莫昔芬或雷洛昔芬，这些药物在一些使用者中会产生严重的副作用。高危女性的预防选择有限，部分原因是我们对导致乳腺癌的生物因素的了解相当初级。此外，我们目前的风险模型只是不准确地估计了 由于缺乏有效和可接受的预防办法，大多数风险较高的妇女没有被确定为癌症高危妇女，也没有提供降低风险的治疗方法。因此，有 迫切需要确定乳房组织中与后续风险相关的生物标记物，这可能有助于改进对高危女性的识别，并促进针对其乳房组织变化的治疗方法的开发。我们建议在一大群基于人群的队列中评估与早期癌前病变和肿瘤启动潜能相关的蛋白质生物标记物对乳腺癌后续风险的贡献。自1996年以来接受良性乳腺活检的近15,000名女性在2009年之前一直被新墨西哥州肿瘤登记处跟踪调查，这是一个由NCI赞助的SEER(监测、流行病学、最终结果)网站，自1968年以来一直在收集新墨西哥州的癌症信息。进行了一项嵌套病例对照研究，将患乳腺癌的妇女与三名对照进行匹配。应用免疫组织化学方法对85例乳腺癌患者和245例对照的良性活检组织中20种蛋白生物标志物的表达进行了评估。已知包括的生物标记物在促成癌症发生的最早事件的途径中是活跃的。我们在这个提案中的目标是完成免疫组织化学染色的病理学家评分，分析数据，并提交发表。我们的努力将包括优化新的方法来确定几个生物标志物的同时存在，以促进在未来的流行病学研究中进行这种评估。我们的研究可以服务于两个重要的目的：(1)改进风险模型，以更准确地区分哪些女性将会(或不会)继续罹患乳腺癌；(2)识别可能作为新预防措施发展目标的恶性潜在生物标志物。我们在这笔赠款中的目标是更准确地区分乳腺癌高危女性，至少在肿瘤病理检测前几年，当预防措施可能合理地阻止或推迟其发展时，并提供特定癌症相关途径中生物标记物表达的信息，这可能会指导量身定做的预防工作。

DESCRIPTION (provided by applicant): While a substantial proportion of women in the U.S. are considered at 'high risk' for breast cancer during their lifetime (Graubard 2010), most will never develop breast cancer. Women considered at high risk face mostly difficult choices to keep cancer at bay. Some are eligible for endocrine therapies such as Tamoxifen or Raloxifene, which have been associated with serious side effects in some users. Prevention options for high risk women are limited in part because our understanding of biological factors that cause breast cancer is fairly elementary. In addition, our current risk models only imprecisely estimate risk of subsequent cancer, and because effective and acceptable prevention options are scarce, most women at higher risk are not identified as such, or offered risk reducing therapies. Thus, there is a critical need to identify biomarkers in breast tissue that are related to subsequent risk, which may facilitate improved identification of women at high risk, and prompt development of therapies that are specific to their breast tissue changes. We propose to evaluate the contribution of protein biomarkers associated with early precancerous changes and tumor-initiating potential to subsequent risk of breast cancer among a large population-based cohort. Almost 15,000 women who received benign breast biopsies since 1996 were followed for breast cancer until 2009 by the New Mexico Tumor Registry, an NCI-sponsored SEER (Surveillance, Epidemiology, End Results) site that has been gathering information on cancer in New Mexico since 1968. A nested case-control study was conducted, and women who developed breast cancer were matched to three controls. An initial 85 breast cancer cases and 245 controls were evaluated for expression of 20 protein biomarkers in their benign biopsy tissue using immunohistochemistry. Included biomarkers are known to be active in pathways contributing to the earliest events in carcinogenesis. Our goal in this proposal is to complete the pathologist scoring of the immunohistochemical staining, analyze the data, and submit them for publication. Our efforts will include optimization of novel methods to determine the simultaneous presence of several biomarkers, to facilitate such assessment in future epidemiologic studies. Our study can serve two important purposes: (1) To improve risk models to more precisely distinguish women who will (and will not) go on to breast cancer; and (2) To identify biomarkers of malignant potential that may serve as targets for development of new prevention initiatives. Our goal in this grant is to more precisely distinguish women at high risk of breast cancer at least several years before pathologic detection of the tumor, when prevention might reasonably deter or delay its' development, and to provide information on biomarker expression in specific cancer-related pathways, which might guide tailored prevention efforts.