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.

总结 我的职业目标是成为一名独立的癌症流行病学家，使用分子方法，包括 分子病理学，以了解癌症的病因，在整个人口和不同种族和 少数民族。虽然我的博士研究集中在与肺，前列腺， 和结直肠癌，抵达罗斯韦尔公园癌症研究所（RPCI），我意识到许多 乳腺癌研究的复杂性和未回答的问题，特别是在非洲裔美国人（AA）中 女性，受不利的乳腺癌亚型影响最大的人群，即，雌激素受体阴性 (ER-)三阴性和基底样肿瘤。随着对乳腺癌亚型及其 由于评估风险因素和结果的重要性，我开始有动力更多地了解病理学， 研究肿瘤水平的特征。然而，很明显，要在这一领域取得成功，我 需要更多的病理学知识和经验以及评估亚型的分子方法 和肿瘤的分子标记。因此，通过这个K 07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。在乳腺癌的危险因素中，肥胖和中心性肥胖是 与AA女性乳腺癌风险相关，这些相关性可能在肿瘤之间存在差异。 亚型然而，这些关联的基本机制在很大程度上尚不清楚。正能量 不平衡，肥胖的一个原因，可以激活磷脂酰肌醇3-激酶/AKT/哺乳动物的目标， 雷帕霉素（mTOR）途径，其在调节细胞生长和增殖中是重要的，并且已经被 与乳腺癌的发展有关为了更好地了解mTOR通路在肿瘤发生中的作用， 肥胖和乳腺癌亚型之间的关联，我将进行分子病理流行病学研究， 利用来自1，400名AA和433名欧美（EA）乳腺癌女性的肿瘤组织和数据的研究 女性健康圈研究（WCHS）中的癌症，目前由R 01 CA 185623支持。我的目标是 检查ER+和ER-乳腺肿瘤之间以及内源性乳腺癌之间mTOR通路活性的差异。 亚型，其包括管腔A、管腔B、人表皮生长因子受体2（HER 2）- 过度表达和基底细胞样肿瘤（Aim 1）。这项研究还将评估 mTOR通路活性与肥胖的关键成分（全身性肥胖、中心性肥胖、身体肥胖）的关系 AA女性（目标2）中的组成和体重增加），并比较mTOR通路的相关性 活动与乳腺癌亚型，以及肥胖，AA和EA妇女之间（探索性目的）。 这项研究的期望是提供一个更好的了解在何种程度上肥胖的组成部分， 与mTOR通路活动相关;是否更频繁地观察到 AA女性中的特定乳腺癌亚型;以及AA和EA之间这些相关性是否不同 妇女此外，我们预计这项研究将阐明ER-，三阴性， AA妇女的基底样乳腺癌，这可能有助于减少乳腺癌死亡率的差距 AA和EA的区别该项目的结果将作为开发R 01的垫脚石 该项目可能会扩展到检查其他肥胖相关途径中的分子组织标记物， 非裔美国人乳腺癌流行病学和风险（AMBER）联盟，NCI计划项目赠款 (P01 CA 151135）。建议的研究项目是为我量身定制的，以应用知识和技能， 将从培训活动中获得，我的主要导师，克莉丝汀安布罗松博士，谁是一个世界- 分子流行病学和乳腺癌病因学和差异方面的著名专家，以及 WCHS和AMBER Consortium我也将受益于我的共同导师：Thaer Khoury博士（乳腺癌 病理学）、Song Liu博士（肿瘤标志物数据的统计分析）和Elisa Bandera博士（乳腺癌 肥胖的病因学和种族差异）。为了进一步的指导，我请了分子病理学家的专家， 博士Wiam Bashara和Deborah Erwin博士就在少数群体中传播结果进行协商。 培训活动包括病理学课程，在分子病理学实验室进行为期六个月的轮换， 与Khoury博士定期进行办公室轮换，出席研究所和国际会议并发表演讲 会议，分子病理流行病学出版物，R 03和R 01资助写作， 道德/研究行为，以及参与工作组和数据收集活动。研究 项目和实验室轮换将由P-30 CCSG病理资源网络共享支持 资源，这也是积极参与WCHS和琥珀财团。长期合作伙伴关系 RPCI的病理学和癌症预防和控制部门之间，以及多学科 RPCI的乳腺癌研究设置，以及布法罗的纽约大学的州立大学， 为我实现我的研究和职业目标提供了一个出色的环境。