Prevention of ER-negative Breast Cancer: Identification*

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癌症的高危女性患浸润性乳腺癌的风险。然而，在这些女性中，抗雌激素并不能降低雌激素受体阴性乳腺癌的发生率。因此，迫切需要确定和测试可以防止ER阴性乳腺癌发展的药物。虽然ER阴性的乳腺细胞对雌激素没有反应，但它们确实需要EGF、TGFpha和IGF-I等生长因子，因此传递这些生长因子信号的分子是治疗和预防ER阴性乳腺癌的药物的靶点。特别有希望预防ER阴性乳腺癌的药物包括维甲酸和信号转导抑制剂，如酪氨酸激酶抑制剂和COX-2抑制剂。这些药物在体外都会抑制癌细胞的生长，并会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，这些药物可以抑制体内乳腺癌的发展，在发生ER阴性乳腺癌的小鼠模型中。我们现在提出三个目标来检验这一假设，即这些药物成功的化学预防将与乳腺组织中特定生物标记物的调节有关。我们将：1)在三种与人ER阴性乳腺癌相关的小鼠模型(C3(1)-SV40Tag、MMTV-c-erbB2和P53缺失乳腺移植模型)中，比较分子靶向化学预防性药物抑制ER阴性乳腺癌发展的能力；2)通过基因组学(SAGE)和蛋白质组学技术确定受化学预防性药物调控的乳腺组织生物标记物，这些生物标记物被发现有效地抑制了小鼠ER阴性乳腺癌的形成；以及3)建立了这些标记物的基于RNA和蛋白质的分析，并验证了有效药物在小鼠乳腺和人乳腺细胞中对这些生物标记物的调控。这些生物标记物将在未来的化学预防临床试验中用作标记物，以测试有前景的分子靶向制剂。

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.