Alternative Mechanisms to Inactivate p53 During Oncogenesis

描述（由申请人提供）：尽管在约50%的人类癌症中发现了p53突变，但在某些癌症类型（如乳腺癌）中p53突变的比例要低得多。具有野生型p53的癌症中的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这些替代机制可以为大部分携带野生型p53的癌症的肿瘤发生的分子机制提供进一步的见解。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，BCCIP表达的缺乏与一组具有野生型p53的癌症中的不良临床结果相关，但在具有突变型p53的癌症中不相关。33%的乳腺癌中BCCIP表达缺失，并且BCCIP阴性与乳腺癌中的野生型p53相关。这些临床数据与BCCIP缺陷可能减轻野生型p53功能的发现一致，并表明p53和BCCIP在功能上处于相同的上位途径，以调节癌症治疗的结果和乳腺癌亚组的发展。基于这些研究，我们假设BCCIP缺陷代表了抑制p53肿瘤抑制活性的新机制，并在乳腺癌的发展中发挥作用。目的1测试的工作假设，BCCIP所需的p53结合靶向启动子。当BCCIP受损时，p53不能有效地形成四聚体，因此不能作为肿瘤抑制因子正常发挥作用。目的2建立两种乳腺肿瘤发生模型，探讨BCCIP缺陷在乳腺癌发生中的作用，特别是在三阴性乳腺癌和p53野生型乳腺癌中的作用。由于在大部分乳腺癌中发现BCCIP下调，并且BCCIP缺陷可能通过废除野生型p53功能而赋予对治疗性DNA损伤的抗性，因此我们相信这项研究具有进一步了解肿瘤发生的分子机制的巨大潜力，特别是对于这些具有野生型p53的癌症，因此将对改善癌症干预产生重大影响。 公共卫生相关性：肿瘤抑制基因p53在肿瘤中的状态是决定肿瘤发生和治疗结果的主要因素。我们的研究将阐明BCCIP缺陷减轻野生型p53肿瘤抑制功能的机制和后果。由于BCCIP在相当一部分人类癌症中缺乏表达（例如，基于我们的初步研究，约33%的乳腺癌），约50%的人类癌症不存在p53突变，我们的研究将揭示与大部分人类癌症相关的分子肿瘤发生机制，并为进一步开发癌症干预提供科学依据。

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. PUBLIC HEALTH RELEVANCE: It is well established that the status of tumor suppressor p53 in cancer is a major factor dictating the tumorigenesis and therapeutic outcomes. Our study will address the mechanisms and the consequences of BCCIP defect in alleviating wild type p53 tumor suppressor function. Because lack of BCCIP expression is found in a significant portion of human cancer (for example ~33% of breast cancer based on our preliminary studies) and ~50% of all human cancers do not have p53 mutation, our study will reveal a molecular oncogenesis mechanism relevant to a large portion of human cancers, and offer the scientific bases for further development of cancer intervention.