Prevention of Estrogen Receptor-negative Breast Cancer

预防雌激素受体阴性乳腺癌

• 批准号: 7231999
• 负责人: POWEL H BROWN
• 金额: $ 47.59万
• 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 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231999
• 关键词: Prevention; Estrogen; Receptor; negative; Breast

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，抗雌激素可以降低没有现有癌症的高风险女性侵入性乳腺癌的风险。然而，抗雌激素不会降低这些女性雌激素受体负乳腺癌的发生率。因此，迫切需要识别和测试将防止ER阴性乳腺癌发展的剂。尽管ER阴性乳腺细胞对雌激素没有反应，但它们确实需要EGF，TGFALPHA和IGF-I等生长因子，因此转导这些生长因子信号的分子是瓷砖治疗和预防ER阴性乳腺癌的靶标。预防ER阴性乳腺癌的特别有希望的药物包括类视感和信号转导抑制剂，例如酪氨酸激酶抑制剂和COX-2抑制剂。这些药物都抑制了体外癌细胞的生长，并将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，这些药物可以抑制发展ER阴性乳腺癌的小鼠模型中体内乳腺癌的发展。现在，我们提出的三个旨在检验以下假设：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有关。我们将：1）比较分子靶向化学预防剂的能力，抑制与人类ER阴性乳腺癌相关的三种小鼠模型中ER阴性乳腺癌的发展（C3（1）-SV40TAG，MMTV-C-ERBB2和P53 NULL乳腺乳腺乳腺移植模型）； 2）通过基因组（SAGE）和蛋白质组学技术识别乳腺组织生物标志物，这些乳腺生物标志物受到化学预防剂的调节，可有效抑制小鼠模型中的ER阴性乳腺肿瘤形成； 3）为这些标记物开发基于RNA和蛋白质的测定法，并通过小鼠乳腺和人类乳腺细胞中有效的生物标志物来验证这些生物标志物的调节。然后，这些生物标志物将在未来的化学预防临床试验中用作标记，以测试有希望的分子靶标。

项目成果

Prevention of ER-negative breast cancer.

• DOI: 10.1007/978-3-540-69297-3_13
• 发表时间: 2009
• 期刊: Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer

The AP-1 transcription factor regulates postnatal mammary gland development.

• DOI: 10.1016/j.ydbio.2006.03.042
• 发表时间: 2006-07
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: Q. Shen;Yun Zhang;I. Uray;Jamal L Hill;Heetae Kim;Chunhua Lu;M. Young;E. Gunther;S. Hilsenbeck-S.