Prevention of ER-negative Breast Cancer: Identification*

ER 阴性乳腺癌的预防：识别*

• 批准号: 7057822
• 负责人: POWEL H BROWN
• 金额: $ 47.79万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7057822
• 关键词: SDS polyacrylamide gel electrophoresis; biomarker; breast neoplasms; cancer prevention; cell line; chemoprevention; epidermal growth factor; estrogen receptors; female; genetically modified animals; growth factor receptors; immunocytochemistry; laboratory mouse; mammary gland; matrix assisted laser desorption ionization; polymerase chain reaction; proteomics; serial analysis of gene expression; technology /technique development

DESCRIPTION (provided by applicant): Recent clinical trials have shown that antiestrogens can reduce the risk of invasive breast cancer in high-risk women without existing cancer. However, antiestrogens do not reduce the incidence of estrogen receptor negative breast cancers in these women. Thus, there is an urgent need to identify and test agents that will prevent the development of ER-negative breast cancer. While ER-negative breast cells do not respond to estrogen, they do require growth factors such as EGF, TGFalpha, and IGF-I, so that the molecules that transduce these growth factor signals are targets for agents for tile treatment and prevention of ER-negative breast cancer. Particularly promising agents for the prevention of ER-negative breast cancer include retinoids and signal transduction inhibitors, such as tyrosine kinase inhibitors and COX-2 inhibitors. These agents all suppress the growth of cancer cells in vitro, and will inhibit the growth of normal and malignant breast cells. In addition, our preliminary results suggest that these agents can suppress the development of breast cancer in vivo in mouse models that develop ER-negative breast cancer. We now propose three aims to test the hypothesis that successful chemoprevention by these agents will be associated with modulation of specific biomarkers in the mammary gland tissue. We will: 1) compare the ability of molecularly targeted chemo-preventive agents to suppress the development of ER-negative breast cancer in three mouse models relevant to human ER-negative breast cancer (C3(1)-SV40Tag, MMTV-c-erbB2, and p53 null mammary gland transplant models); 2) identify by genomic (SAGE) and proteomic techniques mammary tissue biomarkers that are regulated by chemopreventive agents found to effectively suppress ER-negative mammary tumor formation in the mouse models; and 3) develop RNA- and protein-based assays for these markers and validate the modulation of these biomarkers by effective agents in mouse mammary glands and human breast cells. These biomarkers will then serve as markers in future chemoprevention clinical trials to test promising molecularly targeted agents.

描述（由申请人提供）： 最近的临床试验表明，抗雌激素可以降低未患有癌症的高危女性患浸润性乳腺癌的风险。然而，抗雌激素并不能降低这些女性雌激素受体阴性乳腺癌的发病率。因此，迫切需要鉴定和测试能够预防 ER 阴性乳腺癌发展的药物。虽然 ER 阴性乳腺细胞对雌激素没有反应，但它们确实需要生长因子，例如 EGF、TGFα 和 IGF-I，因此转导这些生长因子信号的分子是治疗和预防 ER 阴性乳腺癌药物的靶标。用于预防 ER 阴性乳腺癌的特别有前景的药物包括类视黄醇和信号转导抑制剂，例如酪氨酸激酶抑制剂和 COX-2 抑制剂。这些药物均能在体外抑制癌细胞的生长，并抑制正常和恶性乳腺细胞的生长。此外，我们的初步结果表明，这些药物可以在发生 ER 阴性乳腺癌的小鼠模型中抑制体内乳腺癌的发展。我们现在提出三个目标来检验以下假设：这些药物的成功化学预防将与乳腺组织中特定生物标志物的调节相关。我们将： 1) 比较分子靶向化学预防药物在与人类 ER 阴性乳腺癌相关的三种小鼠模型（C3(1)-SV40Tag、MMTV-c-erbB2 和 p53 缺失乳腺移植模型）中抑制 ER 阴性乳腺癌发展的能力； 2) 通过基因组 (SAGE) 和蛋白质组学技术鉴定乳腺组织生物标志物，这些生物标志物受化学预防剂调节，发现可有效抑制小鼠模型中 ER 阴性乳腺肿瘤的形成； 3) 针对这些标记物开发基于 RNA 和蛋白质的检测方法，并验证小鼠乳腺和人类乳腺细胞中有效药物对这些生物标记物的调节作用。这些生物标志物将作为未来化学预防临床试验的标志物，以测试有前途的分子靶向药物。