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

摘要 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，了解总体人群和不同种族之间的癌症病因 种族亚群。虽然我的博士研究集中在营养因素与肺，前列腺， 和结直肠癌，当我到达罗斯威尔公园癌症研究所(RPCI)时，我意识到了许多 乳腺癌研究中的复杂性和悬而未决的问题，特别是在非裔美国人(AA)中 女性，受不良乳腺癌亚型影响最大的人群，即雌激素受体阴性 (ER-)、三阴性和基底样瘤。随着对乳腺癌亚型及其相关疾病的认识不断加深 评估风险因素和结果的重要性，我变得有动力学习更多关于病理学和 在肿瘤水平上研究其特点。然而，很快就变得明显的是，要在这一领域取得成功，我 需要更多病理学和分子方法方面的知识和经验来评估亚型 以及肿瘤中的分子标记。因此，通过这个K07机制，我将制定所需的 分子病理流行病学所需的专业知识，包括病理学的实验室经验；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 与再生障碍性贫血女性的乳腺癌风险有关，而且这些相关性在不同的肿瘤之间可能有所不同 子类型。然而，这些关联的潜在机制在很大程度上尚不清楚。正能量 失衡是肥胖的原因之一，可以激活磷脂酰肌醇3-激酶/AKT/哺乳动物靶 雷帕霉素(MTOR)途径，在调节细胞生长和增殖中起重要作用，一直以来 与乳腺癌的发展有关。为了更好地了解mTOR通路在 肥胖与乳腺癌亚型的关系，我将进行分子病理流行病学研究 利用1400名AA和433名患有乳房的欧美妇女的肿瘤组织和数据进行的研究 妇女健康圈癌症研究(WCHS)，目前由R01 CA185623支持。我的目标是 检查ER+和ER-乳腺肿瘤以及固有肿瘤之间mTOR通路活性的差异 亚型，包括腔A，腔B，人表皮生长因子受体2(HER2)- 再生障碍性贫血妇女中的过度表达和基底样瘤(目标1)。这项研究还将评估这种联系 MTOR途径活动与肥胖的关键组成部分(一般肥胖、中心性肥胖、身体 成分和体重增加)，并比较mTOR途径的相关性 AA和EA女性之间乳腺癌亚型和肥胖的活动(探索性目标)。 这项研究的期望是更好地了解肥胖因素在多大程度上 与mTOR途径活动相关；无论这种关联在 AA女性中的特定乳腺癌亚型；AA和EA之间的这些相关性是否不同 女人。此外，我们预计这项研究将有助于阐明ER阴性、三阴性和 AA女性中的基底样癌，这可能有助于降低乳腺癌死亡率差距 在AA和EA女人之间。该项目的成果将作为开发R01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志物。 非裔美国人乳腺癌流行病学和风险(琥珀)联盟，NCI计划项目赠款 (P01 CA151135)。建议的研究项目为我量身定做，以应用以下知识和技能 将从培训活动中获得，我的主要导师克里斯汀·安布罗松博士，她是一个世界- 著名的分子流行病学和乳腺癌病因和差异方面的专家，以及 WCHS和琥珀联盟。我还将受益于我的共同导师：塞尔·库里博士(乳腺癌 病理学)、宋柳博士(肿瘤标记物数据的统计分析)和ELISA Bandera博士(乳腺癌 肥胖和种族差异的病因学)。为了得到进一步的指导，我征集了分子病理学家的专业意见， Wiam Bashara博士和Deborah Erwin博士就结果在少数群体中的传播进行了磋商。 培训活动包括病理学课程，在分子病理学实验室轮换六个月， 与Khoury博士定期在办公室轮换，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，R03和R01赠款撰写，继续培训 研究的道德操守/进行，以及参加工作组和数据收集活动。这项研究 项目和实验室轮换将由共享的P-30 CCSG病理资源网络提供支持 资源，它还积极参与WCHS和琥珀联盟。长期存在的伙伴关系 在RPCI的病理学和癌症预防控制部门之间，以及多学科之间 以及纽约州立大学布法罗分校的乳腺癌研究环境， 为我实现我的研究和职业目标提供一个出色的环境。

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.