Alternative Mechanisms to Inactivate p53 During Oncogenesis

描述(申请人提供)：虽然在所有人类癌症中发现了约50%的p53突变，但在某些癌症类型(如乳腺癌)中，p53突变所占的比例要低得多。野生型P53癌中的P53功能可以通过其他机制来规避。识别这些P53肿瘤抑制功能受损的替代机制可以进一步深入了解大部分携带野生型P53的癌症发生的分子机制。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序列的结合以及野生型P53的反式激活活性受到严重抑制。此外，在一组野生型p53癌中，缺乏BCCIP表达与较差的临床结果有关，而在突变p53癌中则不相关。BCCIP在33%的乳腺癌中不表达，且BCCIP阴性与乳腺癌中野生型P53的表达有关。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，并提示P53和BCCIP在功能上处于相同的上位通路，调节癌症治疗的结果和乳腺癌亚群的发展。基于这些研究，我们假设BCCIP缺陷代表了一种新的失活P53抑癌基因活性的机制，并在乳腺癌的发生发展中发挥了作用。目的1验证P53与靶向启动子结合需要BCCIP的工作假说。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发挥作用。目的2将建立两个乳腺肿瘤发生模型，以研究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。由于BCCIP下调在很大一部分乳腺癌中被发现，而BCCIP缺陷可能通过取消野生型P53的功能而对治疗性DNA损伤产生抵抗，我们相信这项研究对于进一步了解肿瘤发生的分子机制，特别是对于那些携带野生型P53的乳腺癌，将具有重要的影响。

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.