Retrospective validation of putative breast cancer predictive molecular markers

假定的乳腺癌预测分子标志物的回顾性验证

• 批准号: 7459008
• 负责人: Indira none Poola
• 金额: $ 14.8万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459008
• 关键词: Awareness; Benign; Biological Markers; Breast; Cancer Death Rates; Cancer Etiology; Cancer Patient; Cancerous; Cells; Cessation of life; Clinical; Collection; Control Groups; Data; Death Rate; Detection; Development; Diagnosis; Diagnostic; Ductal; Ductal Epithelial Cell; Early Diagnosis; Environment; Fine needle aspiration biopsy; Gene Expression; Goals; Health Care Costs; High-Risk Cancer; Immunohistochemistry; Incidence; Interstitial Collagenase; Invasive; Irrigation; Knowledge; Lead; Lesion; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Messenger RNA; Morphology; Noninfiltrating Intraductal Carcinoma; Numbers; Outcome; Palpable; Pathologist; Patients; Polymerase Chain Reaction; Premalignant; Procedures; Proteins; Range; Rate; Recording of previous events; Research; SPAM1 gene; Sampling; Screening procedure; Second Primary Cancers; Staging; Surgical Oncologist; Testing; Time; Tissues; United States; Validation; Woman; Work; base; cancer diagnosis; expectation; follow-up; innovation; malignant breast neoplasm; mortality; success; tool; tumor

DESCRIPTION (provided by applicant): Although there is a slight decline in the deaths from invasive breast cancer in recent years, it continues to be the most diagnosed cancer and the second leading cause of cancer deaths for women in the US. We can expect a significant reduction in the death rate if the cancer is detected and treated at the precancerous stage. However, there are no known markers to detect a precancerous stage or predict which precancerous lesions will develop into IBC. We recently identified over 300 putative breast cancer predictive molecular markers by global gene expression analysis of precancerous lesions from patients with and without the history of cancer. However, it is not known which of the 300 putative markers could be applied for detecting a 'True Precancerous Stage' and predicting cancer development unless they are validated. Our long range goal is to reduce mortality rate with breast cancer, by detecting at the precancerous stage. The objective of this application is to establish that at least three of the putative markers could be applied as breast cancer predictive markers. Our rationale that the putative markers that were identified by us could be applied as predictive markers was based on our preliminary data obtained using limited number of archival precancerous lesions. Our data suggested that three of the putative markers were highly expressed in precancerous tissues from patients who later developed cancer and were absent in the control group. We will accomplish the objective of this application by pursuing two specific aims: 1) Establish that elevated expression of at least three putative markers is associated with subsequent development of cancer using archival precancerous tissues and by immunohistochemistry, 2) Establish that the validated markers could be detected at their mRNA levels in mostly atypical cells and a small percentage of benign cells obtained by ductal lavage collection procedure by RT real-time PCR. The rationale for the proposed work is that 1) once we establish that elevated expression of the predictive markers is associated with subsequent development of breast cancer, that information could be used for screening precancerous lesions and identifying patients with lesions that may develop into cancer, and 2) the validated markers could be used for screening women with no lesions using samples of ductal cells obtained by procedures such as ductal lavage collection and identifying those at very high risk of cancer development. The proposed work is innovative, because predictions on cancer development will be based on the expression of a group of molecular markers instead of histological diagnosis of precancerous lesions. It capitalizes on the putative breast cancer markers identified by us which to our knowledge not done by any one else. It is our expectation that elevated expression of the putative molecular markers will predict cancer development and those molecules could be detected in ductal lavage by RT real-time PCR. The outcomes will be significant, because it is expected that the new knowledge could be applied to detect cancer at the precancerous stage before mammographically detectable or palpable tumor are formed. Detection and treatment at the precancerous stage will have a major impact in reducing the deaths from cancer, simultaneously cutting down the health care cost. The current project is to identify markers that detect a pre-cancerous stage and predict development of breast cancer in women who have mammographically detectable benign lesions as well as in women who have no mammographically detectable lesions. Detection at the precancerous stage and treatment could lead to fewer incidences of breast cancer and deaths from it.

描述（由申请人提供）：尽管近年来浸润性乳腺癌的死亡率略有下降，但它仍然是美国女性诊断最多的癌症和癌症死亡的第二大原因。如果癌症在癌前阶段被发现和治疗，我们可以预期死亡率会显著降低。然而，没有已知的标志物来检测癌前阶段或预测哪些癌前病变将发展成IBC。我们最近通过对有和没有癌症史的患者的癌前病变进行全球基因表达分析，确定了300多个推定的乳腺癌预测分子标记。然而，目前还不知道300个假定的标志物中的哪一个可以用于检测“真正的癌前阶段”和预测癌症的发展，除非它们被验证。我们的长期目标是通过在癌前阶段进行检测来降低乳腺癌的死亡率。本申请的目的是确定至少三种推定的标志物可以用作乳腺癌预测标志物。我们认为我们鉴定的推定标志物可以用作预测标志物的理由是基于我们使用有限数量的存档癌前病变获得的初步数据。我们的数据表明，三个假定的标记物在后来发展成癌症的患者的癌前组织中高度表达，而在对照组中不存在。我们将通过追求两个具体目标来实现本申请的目标：1）使用存档的癌前组织并通过免疫组织化学确定至少三种推定标志物的表达升高与癌症的后续发展相关，（二）确定经验证的标志物可以在大多数非典型细胞和通过导管灌洗收集获得的一小部分良性细胞中的mRNA水平上检测到通过RT实时PCR方法。所提出的工作的基本原理是：1）一旦我们确定预测标志物的表达升高与乳腺癌的后续发展相关，则该信息可用于筛查癌前病变并识别具有可能发展为癌症的病变的患者，和2）经验证的标记物可用于使用通过诸如导管灌洗收集的程序获得的导管细胞样品来筛查没有病变的妇女，识别那些癌症发展风险非常高的人。这项工作是创新的，因为对癌症发展的预测将基于一组分子标记物的表达，而不是癌前病变的组织学诊断。它利用了我们确定的假定乳腺癌标志物，据我们所知，其他任何人都没有这样做。我们预期，假定的分子标记物的表达升高将预测癌症的发展，并且这些分子可以通过RT实时PCR在导管灌洗液中检测到。结果将是显著的，因为预计新知识可以应用于在乳房X线摄影可检测或可触及的肿瘤形成之前的癌前阶段检测癌症。癌前阶段的检测和治疗将对降低癌症死亡率产生重大影响，同时降低医疗保健成本。目前的项目是确定检测癌前阶段的标志物，并预测乳腺癌的发展，在妇女谁有乳房X光检查可检测的良性病变，以及在妇女谁没有乳房X光检查可检测的病变。在癌前阶段进行检测和治疗可以减少乳腺癌的发病率和死亡人数。

项目成果

Molecular constitution of breast but not other reproductive tissues is rich in growth promoting molecules: a possible link to highest incidence of tumor growths.

• DOI: 10.1016/j.febslet.2009.08.021
• 发表时间: 2009-09-17
• 期刊: FEBS LETTERS
• 影响因子: 3.5
• 作者: Poola, Indira;Abraham, Jessy;Marshalleck, Josephine J.;Yue, Qingqi;Fu, Sidney W.;Viswanath, Lokesh;Sharma, Nikhil;Hill, Russel;DeWitty, Robert L.;Bonney, George
• 通讯作者: Bonney, George