Roles for ING4 as a tumor suppressor in breast cancer

描述（由申请人提供）：乳腺癌是女性中最常见的癌症。对于雌激素受体阳性的肿瘤患者，早期发现后进行肿瘤切除术和他莫昔芬治疗，虽然提高了治愈率，但对于初次治疗5年内肿瘤复发的患者，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，可以开发出针对与个体肿瘤相关的特定分子病变的更好的治疗方法。本研究的目的是确定ING4作为肿瘤抑制因子在乳腺癌中的作用，并阐明ING4功能的分子机制。这个建议是候选人最近发表的作品的直接延续。候选人在一种新的肿瘤抑制筛选中发现ING4是一种可以抑制接触抑制丧失的基因。候选人表明，ING4在各种人类癌细胞系中发生突变，并且在10-20%的乳腺癌细胞系以及原发性乳腺肿瘤中缺失。拟开展的研究的具体目的包括：1)利用乳腺癌小鼠模型确定ING4作为肿瘤抑制因子的作用；2)通过鉴定和分析ING4结合蛋白（IBPs）来阐明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。本研究中产生的小鼠系和试剂可直接用于开发靶向ING4通路的癌症治疗方法。

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.