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.

乳腺癌经常与p53基因中的突变有关。 p53突变的存在和表皮生长的过表达因子受体（EGFR）和增殖细胞核抗原（PCNA）表明乳腺癌的预后不良。大量乳腺癌，p53基因中的突变也伴随着 EGFR和PCNA的过表达。有趣的是，唯一已知的肿瘤来源的p53突变体的生化特性是包括EGFR和包括EGFR在内的生长调节基因的反式激活启动子 PCNA。根据此信息，本提案重点介绍研究乳腺癌衍生的p53突变体的假设通过主动放弃钥匙生长的表达来诱导肿瘤发生调节基因和不同的突变体在这种能力上有所不同。这以下是具体目的：（1）确定关系乳腺癌的致癌性和反式激活潜力之间使用人和鼠乳细胞衍生的p53突变体。十六乳房将研究以癌症来源的p53突变体进行比较反式激活和致癌特性。（2）确定不同乳腺癌中p53，EGFR和PCNA水平之间的关系 p53突变与特定目的相同的细胞系 1。（3）确定破坏突变体p53基因对生长特性以及乳房的EGFR和PCNA水平肿瘤细胞。（4）确定转录的机制 p53突变体的激活。了解分子机制突变体p53介导的启动子激活可能阐明突变体p53介导的肿瘤发生。这些研究应允许扩大乳腺癌研究朝着新的方向，应该澄清这些之间的关系乳腺癌预后中的三种蛋白质。了解单个p53突变体的特性可能会帮助肿瘤学家决定乳腺癌患者的治疗过程。突变体的结果 p53干扰实验可能会为靶向突变体开辟未来的途径乳腺癌的p53。