Roles for ING4 as a tumor supressor in breast cancer

描述（由申请人提供）：乳腺癌是女性中最常见的癌症。虽然早期发现后切除肿瘤和雌激素受体阳性肿瘤患者的他莫昔芬治疗提高了治愈率，但在初次治疗后5年内复发肿瘤的患者的生存率急剧下降。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，可以开发出更好的治疗方法，靶向与个体肿瘤相关的特定分子病变。该提案的目的是确定ING 4在乳腺癌中作为肿瘤抑制因子的作用，并阐明ING 4功能的分子机制。这一建议是候选人最近发表的工作的直接延续。该候选人将ING 4鉴定为可以在新型肿瘤抑制剂筛选中抑制接触抑制丧失的基因。该候选人表明，ING 4在各种人类癌细胞系中发生突变，并在10-20%的乳腺癌细胞系以及原发性乳腺肿瘤中缺失。拟议研究的具体目的包括：1）使用乳腺癌小鼠模型确定ING 4作为肿瘤抑制因子的作用; 2）通过鉴定和功能分析ING 4结合蛋白（IBP）来阐明ING 4功能的分子机制。小鼠模型研究的结果将与携带ING 4缺陷的人乳腺肿瘤的病理学相关。在所提出的研究中产生的小鼠系和试剂可直接用于开发靶向ING 4通路的癌症疗法。 拟议的研究将在5年内完成。加州大学旧金山分校的Michael Bishop博士将在前2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。毕晓普博士是候选人的理想导师，他在这个问题上很有权威。然后，候选人将过渡到相当于助理教授的独立学术职位，并继续完成拟议的研究。拟议的研究还将为候选人的研究计划提供一个框架，作为助理教授，以进一步表征她在肿瘤抑制筛选中确定的其他新型候选肿瘤抑制因子。

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.