mTOR pathway in breast cancer subtypes by race: A molecular pathological study

不同种族乳腺癌亚型中的 mTOR 通路：分子病理学研究

• 批准号: 9307737
• 负责人: Ting-Yuan Cheng
• 金额: $ 13.72万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-13 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9307737
• 关键词: 1-Phosphatidylinositol 3-Kinase; Academic/Teacher Award; Address; Affect; African American; Age; American; Animals; Area; Awareness; Biological; Body Composition; Body Size; Body fat; Body mass index; Breast Cancer Epidemiology; Breast Cancer Risk Factor; Buffaloes; Cancer Center Support Grant; Cancer Control; Cancer Etiology; Cell Proliferation; Central obesity; Clinical; Colorectal Cancer; Consultations; Data; Data Collection; Development; Environment; Epidemiologist; Epidemiology; Epidermal Growth Factor Receptor; Estrogen Receptor Status; Estrogen Receptors; Estrogen receptor negative; Ethics; European; Fatty acid glycerol esters; Genetic Polymorphism; Goals; Grant; Growth Factor; Health; High Prevalence; Human; Hyperinsulinism; Image Analysis; Immunohistochemistry; Information Dissemination; Institutes; Insulin Resistance; International; Knowledge; Laboratories; Learning; Light; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mammary Neoplasms; Measures; Mentors; Methods; Minority Groups; Molecular; Molecular Epidemiology; New York; Nutritional; Obesity; Outcome; Pathologic; Pathologist; Pathology; Pathway interactions; Play; Population; Prevention strategy; Program Research Project Grants; Proto-Oncogene Proteins c-akt; Publications; Race; Regulation; Research; Research Personnel; Research Project Grants; Resource Sharing; Resources; Risk Factors; Role; Roswell Park Cancer Institute; Rotation; Sample Size; Sirolimus; Statistical Data Interpretation; Stimulus; Tissue Microarray; Tissues; Training; Training Activity; Tumor Markers; Tumor Subtype; Tumor Tissue; Universities; Waist-Hip Ratio; Weight; Weight Gain; Woman; Writing; anticancer research; base; cancer health disparity; cancer prevention; cancer risk; cancer subtypes; career; career development; cell growth regulation; design; epidemiology study; expectation; experience; laboratory experience; malignant breast neoplasm; meetings; molecular marker; molecular pathology; mortality; multidisciplinary; overexpression; protein expression; public health intervention; racial and ethnic; racial disparity; reproductive; response; skills; study characteristics; tumor; vector; waist circumference; working group

Summary My career goal is to become an independent cancer epidemiologist using molecular approaches, including molecular pathology, to understand cancer etiology in the overall population and among different racial and ethnic sub-populations. While my doctoral research focused on nutritional factors in relation to lung, prostate, and colorectal cancers, upon arrival to Roswell Park Cancer Institute (RPCI), I became aware of the many complexities and unanswered questions in breast cancer research, particularly among African-American (AA) women, the population affected most by unfavorable breast cancer subtypes, i.e., estrogen receptor negative (ER–), triple-negative, and basal-like tumors. With a growing understanding of breast cancer subtypes and its importance in assessing risk factors and outcomes, I became motivated to learn more about pathology and studying characteristics at the tumor level. However, it soon became obvious that to succeed in this area, I needed more knowledge and experience in pathology and the molecular methods used in assessing subtypes and molecular markers in tumors. Therefore, through this K07 mechanism, I will develop the required expertise needed in molecular pathological epidemiology, including laboratory experience in pathology, and further train in breast cancer etiology. Among breast cancer risk factors, obesity and central adiposity are associated with breast cancer risk among AA women, and these associations may differ between tumor subtypes. However, the underlying mechanisms of the associations are largely unclear. Positive energy imbalance, a cause of obesity, can activate the phosphatidylinositol 3-kinase/AKT/mammalian target of the rapamycin (mTOR) pathway, which is important in regulation of cell growth and proliferation and has been implicated in breast cancer development. To better understand the role of the mTOR pathway in the association between obesity and breast cancer subtypes, I will conduct a molecular pathological epidemiology study leveraging tumor tissue and data from 1,400 AA and 433 European-American (EA) women with breast cancer in the Women’s Circle of Health Study (WCHS), currently supported by R01 CA185623. I aim to examine differences in mTOR pathway activities between ER+ and ER- breast tumors and between intrinsic subtypes, which include luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)- overexpressing, and basal-like tumors, among AA women (Aim 1). The study will also assess the association of mTOR pathway activities with key components of obesity (general obesity, central adiposity, body composition, and weight gain) among AA women (Aim 2), and compare the associations of mTOR pathway activities with breast cancer subtypes, as well as with obesity, between AA and EA women (Exploratory Aim). The expectation of this research is to provide a better understanding of the extent to which obesity components are associated with mTOR pathway activities; whether the associations are more frequently observed for specific breast cancer subtypes in AA women; and whether these associations differ between AA and EA women. Also, we anticipate this research to shed light on preventive strategies for ER–, triple-negative, and basal-like breast cancer in AA women, which could assist in reducing the gap of breast cancer mortality between AA and EA women. The results of this project will serve as a stepping stone to developing a R01 project, which is likely to extend to examining molecular tissue markers in other obesity-related pathways in the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, a NCI Program Project grant (P01 CA151135). The proposed research project is well tailored for me to apply the knowledge and skills that will be obtained from training activities, and my primary mentor, Dr. Christine Ambrosone, who is a world- renowned expert in molecular epidemiology and breast cancer etiology and disparities, as well as PI of the WCHS and AMBER Consortium. I will also benefit from my co-mentors: Dr. Thaer Khoury (breast cancer pathology), Dr. Song Liu (statistical analyses in tumor marker data), and Dr. Elisa Bandera (breast cancer etiology in obesity and racial disparities). For further guidance, I enlist the expertise of molecular pathologist, Dr. Wiam Bashara, and from Dr. Deborah Erwin for consultation on result dissemination in minority groups. The training activities include pathology courses, a six-month rotation in molecular pathology laboratories, regular office-based rotations with Dr. Khoury, attendance and presentations at institute and international meetings, publication in molecular pathological epidemiology, R03 and R01 grant writing, continuing training in ethics/conduct of research, and participation in working groups and data collection activities. The research project and laboratory rotation will be supported by the P-30 CCSG Pathology Resources Network Shared Resource, which is also actively involved in the WCHS and AMBER Consortium. The long-existing partnership between the Pathology and Cancer Prevention and Control Departments at RPCI, and the multi-disciplinary setting for breast cancer research at RPCI, as well as the State University of New York University at Buffalo, provide an outstanding environment for me to achieve my research and career goals.

概括 我的职业目标是利用分子方法成为一名独立的癌症流行病学家，包括 分子病理学，了解总体人群以及不同种族和群体之间的癌症病因 虽然我的博士研究重点是与肺、前列腺相关的营养因素， 和结直肠癌，到达罗斯威尔帕克癌症研究所 (RPCI) 后，我意识到许多 乳腺癌研究的复杂性和未解答的问题，特别是在非裔美国人 (AA) 中 女性，受不利乳腺癌亚型（即雌激素受体阴性）影响最严重的人群 (ER–)、三阴性和基底样肿瘤随着对乳腺癌亚型及其的了解不断加深。 由于认识到评估风险因素和结果的重要性，我有动力去了解更多有关病理学和 然而，很快我就发现，要在这一领域取得成功，我需要做的就是研究肿瘤水平的特征。 需要更多的病理学知识和经验以及用于评估亚型的分子方法 因此，通过这个K07机制，我将开发所需的。 分子病理流行病学所需的专业知识，包括病理学实验室经验，以及 进一步培训乳腺癌病因学，其中肥胖和中心性肥胖是乳腺癌的危险因素。 与 AA 女性患乳腺癌的风险相关，并且这些关联在肿瘤之间可能有所不同 然而，这种关联的基本机制尚不清楚。 失衡是肥胖的一个原因，可以激活磷脂酰肌醇 3-激酶/AKT/哺乳动物靶标 雷帕霉素 (mTOR) 通路在细胞生长和增殖的调节中发挥着重要作用， 更好地了解 mTOR 通路在乳腺癌发展中的作用。 肥胖与乳腺癌亚型之间的关联，我将进行分子病理流行病学研究 该研究利用了 1,400 名 AA 和 433 名患有乳腺癌的欧美 (EA) 女性的肿瘤组织和数据 女性健康圈癌症研究 (WCHS)，目前由 R01 CA185623 支持。 检查 ER+ 和 ER- 乳腺肿瘤之间以及内在本质之间 mTOR 通路活性的差异 亚型，包括 Luminal A、Luminal B、人表皮生长因子受体 2 (HER2)- AA 女性中过度表达和基底样肿瘤（目标 1）。 mTOR 通路活性与肥胖关键组成部分（一般性肥胖、中心性肥胖、身体肥胖）的关系 AA 女性（目标 2）中的成分和体重增加），并比较 mTOR 通路的关联 AA 和 EA 女性之间有关乳腺癌亚型以及肥胖的活动（探索性目标）。 这项研究的期望是更好地了解肥胖成分的程度 与 mTOR 通路活性相关；是否更频繁地观察到这种关联 AA 女性的特定乳腺癌亚型；以及 AA 和 EA 之间的这些关联是否存在差异 此外，我们预计这项研究将揭示 ER-、三阴性和女性的预防策略。 AA 女性的基底样乳腺癌，这可能有助于缩小乳腺癌死亡率的差距 AA 和 EA 女性之间的合作 该项目的结果将作为开发 R01 的垫脚石。 项目，该项目可能会扩展到其他肥胖相关途径中的分子组织标记 非裔美国人乳腺癌流行病学和风险 (AMBER) 联盟，NCI 项目资助 （P01 CA151135）拟议的研究项目非常适合我应用所学的知识和技能。 将从培训活动中获得，我的主要导师 Christine Ambrosone 博士是一位世界级的 分子流行病学和乳腺癌病因学和差异方面的著名专家，也是该中心的 PI 我还将受益于我的共同导师 Thaer Khoury 博士（乳腺癌）。 病理学）、刘松博士（肿瘤标志物数据的统计分析）和 Elisa Bandera 博士（乳腺癌） 为了获得进一步的指导，我寻求分子病理学家的专业知识， Wiam Bashara 博士和 Deborah Erwin 博士就少数群体的结果传播进行了咨询。 培训活动包括病理学课程、分子病理学实验室为期六个月的轮换、 与 Khoury 博士定期进行办公室轮换，出席研究所和国际会议并进行演讲 会议、分子病理流行病学出版物、R03 和 R01 拨款写作、继续培训 道德/研究行为，以及参与工作组和数据收集活动。 项目和实验室轮换将由 P-30 CCSG 病理资源网络共享支持 Resource 也积极参与 WCHS 和 AMBER 联盟的长期合作关系。 RPCI 病理学和癌症预防控制部门以及多学科团队之间的合作 RPCI 以及纽约州立大学布法罗分校的乳腺癌研究机构， 为我实现我的研究和职业目标提供了良好的环境。