Alternative Mechanisms to Inactivate p53 During Oncogenesis

描述（由申请人提供）：尽管p53突变存在于约50%的人类癌症中，但p53突变在某些类型的癌症（如乳腺癌）中所占的比例要低得多。p53在野生型p53肿瘤中的作用可通过其他机制规避。这些p53抑瘤功能受损的替代机制的鉴定，可以进一步深入了解大部分携带野生型p53的癌症的肿瘤发生的分子机制。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序列结合，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癌症的不良临床结果相关，而与p53突变型癌症无关。BCCIP在33%的乳腺癌中不表达，BCCIP阴性与野生型p53在乳腺癌中相关。这些临床数据与BCCIP缺陷可能减轻野生型p53功能功能的发现一致，提示p53和BCCIP在功能上处于相同的上位通路，调节癌症治疗结果和乳腺癌亚群的发展。基于这些研究，我们假设BCCIP缺陷代表了一种使p53抑癌活性失活的新机制，并在乳腺癌的发展中发挥作用。目的1验证了BCCIP是p53与靶向启动子结合所必需的工作假设。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将建立两种乳腺肿瘤发生模型，以解决BCCIP缺陷在乳腺癌发展中的作用，特别是在三阴性乳腺癌和p53野生型乳腺癌中。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功能而对治疗性DNA损伤产生抗性，因此我们认为本研究具有很大的潜力，可以进一步了解肿瘤发生的分子机制，特别是对于这些野生型p53的癌症，从而对改善癌症干预具有重要影响。

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.