Roles for ING4 as a tumor suppressor in breast cancer

描述(申请人提供)：乳腺癌是女性最常见的癌症。对于雌激素受体阳性的肿瘤患者，虽然早期发现后切除肿瘤和三苯氧胺治疗提高了治愈率，但初次治疗后5年内复发的患者的存活率大幅下降。通过破译参与乳腺癌发生和发展的癌基因和肿瘤抑制因子，可以开发出更好的针对与个别肿瘤相关的特定分子病变的治疗方法。该建议的目的是确定ING4在乳腺癌中作为肿瘤抑制因子的作用，并阐明ING4功能的分子机制。这项提议是候选人最近发表的工作的直接延续。候选人确认ING4是一种基因，可以在一种新的肿瘤抑制基因筛选中抑制接触抑制的丧失。这位候选人表明，ING4在各种人类癌细胞系中发生突变，在10%-20%的乳腺癌细胞系以及原发乳腺肿瘤中缺失。这项研究的具体目的包括：1)利用小鼠乳腺癌模型确定ING4作为肿瘤抑制因子的作用；2)通过对ING4结合蛋白(IBPs)的鉴定和功能分析，阐明ING4功能的分子机制。小鼠模型研究的结果将与含有ING4缺陷的人类乳腺肿瘤的病理相关联。在拟议的研究中产生的小鼠品系和试剂可以直接用于开发针对ING4途径的癌症治疗。 拟议的研究将在5年内完成。加州大学旧金山分校的Michael Bishop博士将在头两年指导候选人，在此期间，候选人将获得与人类乳腺癌相关的小鼠模型的培训和专业知识。毕晓普博士是这位候选人的理想导师，因为他在这一问题上拥有权威。然后，候选人将过渡到相当于助理教授的独立学术职位，并继续进行拟议的研究，直至完成。拟议的研究还将为候选人作为助理教授的研究计划提供一个框架，以进一步表征她在肿瘤抑制物筛选中确定的其他新的候选肿瘤抑制物。

DESCRIPTION (provided by applicant): Breast cancer is the single most common cancer in women. Although early detection followed by resection of tumors and tamoxifen treatment for estrogen receptor positive tumor patients have improved the cure frequency, the survival rate sharply declines for patients who have recurring tumors within 5 years of initial treatment. By deciphering oncogenes and tumor suppressors involved in the genesis and progression of breast cancer, better therapies can be developed that target specific molecular lesions associated with individual tumors. The objectives of this proposal are to determine roles for ING4 as a tumor suppressor in breast cancer and elucidate molecular mechanisms of ING4 function. This proposal is a direct continuation of the candidate's recently published work. The candidate identified ING4 as a gene that can suppress loss of contact inhibition in a novel tumor suppressor screen. The candidate showed that ING4 is mutated in various human cancer cell lines and is deleted in 10-20% of breast cancer cell lines as well as in primary breast tumors. Specific aims of the proposed studies include: 1) to determine roles for ING4 as a tumor suppressor using mouse models of breast cancer and 2) to elucidate molecular mechanisms of ING4 function by identification and functional analyses of ING4 binding proteins (IBPs). The outcome of the mouse model studies will be correlated with the pathology of human breast tumors that harbor an ING4 deficiency. The mouse lines and reagents generated in the proposed studies can be directly used for the development of cancer therapy targeting the ING4 pathway. The proposed studies are to be completed in 5 years. Dr. Michael Bishop at UCSF will mentor the candidate during the first 2 years, within which time the candidate will acquire training and expertise in mouse models relevant to human breast cancer. Dr. Bishop is an ideal mentor for the candidate with his authority on the subject. The candidate will then transition into an independent academic position equivalent to an assistant professorship and continue the proposed studies to completion. The proposed studies will also provide a framework for the candidate's research program as an assistant professor to further characterize the other novel candidate tumor suppressors that she has identified in her tumor suppressor screen.