BREAST CANCER ETIOLOGY--P53 GAIN OF FUNCTION MUTATIONS

乳腺癌经常与p53基因的突变有关。 P53基因突变与表皮生长的过度表达 因子受体(EGFR)和增殖细胞核抗原(PCNA) 提示乳腺癌预后不良。在相当数量的 乳腺癌，p53基因的突变也伴随着 表皮生长因子受体和增殖细胞核抗原过度表达。有趣的是，唯一已知的 肿瘤来源的p53突变体的生化特性是能够 反式激活生长调节基因的启动子，包括EGFR和 增殖细胞核抗原。根据这一信息，本提案侧重于 乳腺癌来源的P53突变的假说研究 通过主动解除对关键生长因子表达的调控来诱导肿瘤发生 调控基因和不同的突变体在这种能力上是不同的。这个 具体目标如下：(一)确定关系 乳腺癌的致癌性和反式激活潜能之间- 用人和小鼠乳腺细胞衍生的p53突变体。十六个乳房 癌症衍生的p53突变体将被研究以比较 反式激活和致癌特性。(2)确定 不同类型乳腺癌中P53、EGFR和增殖细胞核抗原表达的关系 具有与特定目的研究相同的p53突变的细胞系 1.(3)确定干扰突变型P53基因对细胞的影响 乳房生长特性及其对表皮生长因子受体和增殖细胞核抗原水平的影响 肿瘤细胞。(4)确定转录调控机制(S) P53突变体的激活。对精神分裂症分子机制的理解(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。 这些研究应该允许乳腺癌研究的扩展。 在一个新的方向上，应该澄清这些之间的关系 三种蛋白在乳腺癌预后中的作用了解以下内容 单个p53突变体的特性可能有助于肿瘤学家决定 乳腺癌患者的疗程。突变的结果 P53干扰实验可能开辟未来针对突变体的途径 P53在乳腺癌中的表达。

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.