Biomarkers of Tumor Initiation in Breast Cancer

描述（由申请人提供）：虽然美国相当大比例的女性被认为在其一生中处于乳腺癌的“高风险”（Graubard 2010），但大多数人永远不会患乳腺癌。被认为是高风险的妇女面临着大多数困难的选择，以保持癌症在海湾。有些人有资格接受内分泌治疗，如他莫昔芬或雷洛昔芬，这与一些用户的严重副作用有关。高危女性的预防选择是有限的，部分原因是我们对导致乳腺癌的生物因素的理解是相当初级的。此外，我们目前的风险模型只能不精确地估计 此外，由于缺乏有效和可接受的预防选择，大多数高危妇女没有被确定为高危妇女，也没有得到降低风险的治疗。因此， 迫切需要确定乳腺组织中与后续风险相关的生物标志物，这可能有助于改善对高风险女性的识别，并促进开发针对其乳腺组织变化的治疗方法。我们建议在一个大型人群队列中评估与早期癌前病变和肿瘤启动潜力相关的蛋白质生物标志物对随后乳腺癌风险的贡献。自1996年以来，新墨西哥州肿瘤登记处对近15,000名接受良性乳腺活检的妇女进行了乳腺癌随访，直到2009年。该登记处是一个由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。进行了一项巢式病例对照研究，并将患乳腺癌的妇女与三名对照进行了匹配。最初的85例乳腺癌病例和245例对照使用免疫组织化学评价了其良性活检组织中20种蛋白质生物标志物的表达。已知所包括的生物标志物在促成癌发生的最早期事件的途径中具有活性。我们在本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，并提交出版。我们的努力将包括优化新的方法，以确定同时存在的几个生物标志物，以促进这种评估在未来的流行病学研究。我们的研究可以达到两个重要目的：（1）改进风险模型，以更精确地区分将（和不会）继续患乳腺癌的妇女;（2）确定恶性潜能的生物标志物，这些生物标志物可以作为制定新的预防措施的目标。我们在这项资助中的目标是在肿瘤病理检测之前至少几年更精确地区分乳腺癌高风险女性，当预防可能合理地阻止或延迟其发展时，并提供特定癌症相关途径中生物标志物表达的信息，这可能会指导有针对性的预防工作。

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.