Alternative Mechanisms to Inactivate p53 During Oncogenesis

肿瘤发生过程中 p53 失活的替代机制

• 批准号: 8444595
• 负责人: Zhiyuan Shen
• 金额: $ 9.31万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-14 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444595
• 关键词: Address; Animal Model; BRCA1 gene; BRCA2 gene; Binding; Biochemical; Cancer Biology; Cancer Etiology; Cancer Intervention; Cells; Clinical; Clinical Data; Clinical Research; DNA; DNA Damage; DNA Sequence; Data; Defect; Development; Down-Regulation; Frequencies; Genes; Genetic Epistasis; Goals; Human; Laboratories; Laboratory Study; Malignant Neoplasms; Mammary Tumorigenesis; Modeling; Molecular; Molecular Conformation; Molecular and Cellular Biology; Mus; Mutagenesis; Mutate; Mutation; Outcome; Pathway interactions; Play; Prevention; Protein p53; Proteins; Publishing; Reagent; Regulation; Resistance; Role; Specimen; Testing; Therapeutic; Transgenic Mice; Tumor Suppressor Proteins; Work; base; cancer therapy; cancer type; design; functional status; homologous recombination; improved; insight; malignant breast neoplasm; mouse model; mutant; novel; promoter; public health relevance; therapy development; transcription factor; triple-negative invasive breast carcinoma; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Although p53 mutations are found in ~50% of all human cancers, p53 mutations in some cancer types (such as breast cancer) constitute much lower percentage. The p53 functions among the cancers with wild type p53 can be circumvented by other mechanisms. The identification of these alternative mechanisms by which p53 tumor suppressing function is impaired can provide further insights into the molecular mechanisms of oncogenesis for the large portion of cancers harboring wild type p53. Recent studies suggested that the binding of the wild type p53 with its target promoter DNA sequences, and the trans-activation activity of wild type p53 are severely inhibited when the BCCIP gene is down-regulated. Furthermore, lack of BCCIP expression is associated with a poor clinical outcome in a set of cancer with wild type p53 but not among cancers with mutant p53. BCCIP expression is absent in 33% of breast cancer, and the BCCIP negativity is associated with wild type p53 in breast cancer. These clinical data are consistent with the finding that BCCIP defect may alleviate the function of wild type p53 function, and suggested that p53 and BCCIP are functionally in the same epistatic pathway to modulate the outcomes of cancer treatment and development of a subset of breast cancers. Based on these studies, we hypothesize that BCCIP defect represents a new mechanism to inactivate the p53 tumor suppressor activity, and plays a role in breast cancer development. Aim 1 tests the working hypothesis that BCCIP is required for p53 binding to targeted promoters. When BCCIP is impaired, p53 is not able to form tetramer efficiently thus cannot function properly as a tumor suppressor. Aim 2 will develop two mammary tumorigenesis models to address the role of BCCIP defect in breast cancer development, especially in triple negative breast cancer and the breast cancers that are p53 wild type. Because BCCIP down-regulation is found in a large fraction of breast cancers, and BCCIP defect may confer resistance to therapeutic DNA damage by abrogating the wild type p53 functions, we believe that this study has a great potential to further understand the molecular mechanism of oncogenesis, especially for these cancers with wild type p53, and thus would have significant impact on improving cancer intervention.

描述（由申请人提供）：尽管在所有人类癌症中有50％发现p53突变，但某些癌症类型（例如乳腺癌）中的p53突变构成较低的百分比。具有野生型p53的癌症之间的p53功能可以通过其他机制来规避。鉴定p53肿瘤抑制功能受损的替代机制可以为具有野生型p53的大部分癌症提供对肿瘤发生的分子机制的进一步见解。最近的研究表明，当BCCIP基因下调时，野生型p53与其靶启动子DNA序列的结合以及野生型p53的反式激活活性受到严重抑制。此外，缺乏BCCIP表达与一组野生型p53的癌症中的临床结局差有关，但在患有突变体p53的癌症中不存在。 33％的乳腺癌中没有BCCIP表达，而BCCIP负性与乳腺癌中的野生型p53有关。这些临床数据与BCCIP缺陷可以减轻野生型p53功能的功能的发现是一致的，并建议p53和BCCIP在功能上处于相同的上位途径中，以调节癌症治疗的结果和乳腺癌子集的发展。基于这些研究，我们假设BCCIP缺陷代表了一种使p53肿瘤抑制活性失活的新机制，并在乳腺癌发育中起作用。 AIM 1检验了p53与靶向启动子的结合所必需的工作假设。当BCCIP受损时，p53无法有效形成四聚体，因此无法正常起作用作为肿瘤抑制器。 AIM 2将开发两个乳腺肿瘤发生模型，以解决BCCIP缺陷在乳腺癌发育中的作用，尤其是在三重阴性乳腺癌和p53野生型乳腺癌中。因为在很大一部分乳腺癌中发现了BCCIP下调，并且BCCIP缺陷可能通过废除野生型p53功能来赋予对治疗性DNA损伤的抵抗力，所以我们认为这项研究具有进一步了解癌症生成的分子机制的巨大潜力，尤其是对这些野生型p53的癌症的影响，因此会对野生型p53进行重大影响，并且对改善癌症的癌症会产生重大影响。