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BREAST CANCER ETIOLOGY--P53 GAIN OF FUNCTION MUTATIONS

乳腺癌病因——P53功能获得性突变

基本信息

批准号：
6173283
负责人：
Sumitra Deb
金额：
$ 22.32万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-07-01 至 2002-04-30
项目状态：
已结题

项目摘要

Breast cancer is frequently associated with mutations in the p53 gene. The presence of p53 mutations and overexpression of the epidermal growth factor receptor (EGFR) and proliferating cell nuclear antigen (PCNA) indicate poor prognosis in breast cancer. In a significant number of breast cancers, mutations in the p53 gene are also accompanied by overexpression of EGFR and PCNA. Interestingly, the only known biochemical property of tumor-derived p53 mutants is the ability to transactivate promoters of growth-regulating genes including EGFR and PCNA. On the basis of this information the present proposal focuses on investigating the hypothesis that breast cancer-derived p53 mutants induce oncogenesis by actively deregulating expression of key growth- regulatory genes and different mutants differ in this ability. The following are the Specific Aims: (1) To determine the relationship between oncogenicity and transactivation potential of breast cancer- derived p53 mutants using human and murine mammary cells. Sixteen breast cancer-derived p53 mutants will be studied for comparison of transactivation and oncogenic properties. (2) To determine the relationship between p53, EGFR and PCNA levels in different breast cancer cell lines with p53 mutations identical to those studied in Specific Aim 1. (3) To determine the effects of disrupting the mutant p53 gene on the growth properties as well as on the levels of EGFR and PCNA of breast tumor cells. (4) To determine the mechanism(s) of transcriptional activation by p53 mutants. Understanding the molecular mechanism(s) of mutant p53-mediated promoter activation may elucidate the mechanism of mutant p53-mediated oncogenesis. These investigations should allow for expansion of breast cancer research in a new direction and should clarify the relationship between these three proteins in the prognosis of breast cancer. Knowledge of the properties of the individual p53 mutants may help oncologists decide the course of treatment for the breast cancer patients. Results from mutant p53-disruption experiments may open up future avenues to target mutant p53 in breast cancer.

乳腺癌通常与p53基因突变有关。 p53突变和表皮生长过度表达的存在因子受体（EGFR）和增殖细胞核抗原（PCNA）表明乳腺癌预后不良。在许多乳腺癌，p53基因突变也伴随着 EGFR和PCNA过度表达。有趣的是，唯一已知的肿瘤来源的p53突变体的生物化学性质是能够反式激活生长调节基因的启动子，包括EGFR， PCNA。根据这一资料，本建议的重点是研究乳腺癌来源的p53突变体通过主动去调节关键生长因子表达诱导肿瘤发生- 调节基因和不同的突变体在这种能力上是不同的。的具体目的如下：（1）确定乳腺癌的致癌性和反式激活潜力之间的关系使用人和鼠乳腺细胞衍生p53突变体。十六胸将研究癌症衍生的p53突变体，反式激活和致癌特性。 (2)确定不同类型乳腺癌中p53、EGFR和PCNA表达的相关性研究 p53突变与特定目的中研究的突变相同的细胞系 1. (3)为了确定破坏突变型p53基因对乳腺癌的生长特性以及EGFR和PCNA的表达水平肿瘤细胞 (4)为了确定转录的机制，激活p53突变体。了解的分子机制（S）突变型p53介导的启动子激活可能阐明突变型p53介导的肿瘤发生。这些调查应该允许乳腺癌研究的扩展在一个新的方向，并应澄清这些之间的关系三种蛋白质在乳腺癌预后中的作用知识单个p53突变体的特性可能有助于肿瘤学家决定乳腺癌患者的治疗过程。突变体结果 p53破坏实验可能为靶向突变体开辟未来的途径乳腺癌中的p53