Cholesterol promotes breast cancer progression: establishing the mechanisms

胆固醇促进乳腺癌进展：建立机制

• 批准号: 8804581
• 负责人: Emily Jane Gallagher
• 金额: $ 16.86万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8804581
• 关键词: 25-hydroxycholesterol; Address; ApoE knockout mouse; Apolipoprotein E; Area; Automobile Driving; Award; Basic Science; Biological; Breast Cancer Cell; CYP3A4 gene; Cancer Biology; Cancer Patient; Cell membrane; Cell surface; Cells; Cessation of life; Cholesterol; Clinical Medicine; Clinical Research; Collaborations; Cytokine Signaling; Dedications; Development; Diabetes Mellitus; Diet; Dyslipidemias; ERBB2 gene; Endocrinology; Enzymes; Epidemiologic Studies; Estrogen Receptors; Estrogen receptor positive; Fatty acid glycerol esters; Fellowship; Future; Gene Expression; Genetic; Goals; Growth; Health; Hormone Receptor; Human; Hyperlipidemia; In Vitro; Internal Medicine; Ireland; Knowledge; LDL Cholesterol Lipoproteins; Link; Lipids; Lipoprotein Binding; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; MDA MB 231; Malignant Neoplasms; Mammary Neoplasms; Mediating; Medicine; Mentored Clinical Scientist Development Award (K08); Mentors; Mentorship; Metabolic; Metabolism; MicroRNAs; Mixed Function Oxygenases; Molecular Biology Techniques; Mus; Neoplasm Metastasis; New York; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Patients; Primary Neoplasm; Production; Progesterone Receptors; Rag1 Mouse; Reporting; Research; Research Personnel; Research Project Grants; Resistance; Risk; Role; Scientist; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Time; Training; United States; Universities; Very low density lipoprotein; Woman; base; c-myc Genes; cancer cell; cancer recurrence; cancer risk; career; clinical practice; college; cytokine; epithelial to mesenchymal transition; experience; improved; in vivo; liquid chromatography mass spectrometry; malignant breast neoplasm; medical schools; mortality; mouse model; neoplastic cell; oncology; outcome forecast; overexpression; prevent; professor; receptor expression; research study; rosuvastatin; skills; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor metabolism; tumor progression; uptake

 DESCRIPTION (provided by applicant): The purpose of this K08 Mentored Clinical Scientist Development Award proposal is to describe the five year training, development and mentorship plan for Dr. Emily Gallagher, in addition to her research plans to understand the link between obesity, Type 2 diabetes and breast cancer, specifically by examining the effect of high circulating cholesterol on breast cancer progression. Dr. Gallagher received her MD with honors from the University College Dublin, Ireland. She trained clinically in Ireland before moving to New York and is Board Certified in Internal Medicine and Endocrinology. As a clinician, Dr. Gallagher recognized the importance of basic science research in advancing clinical medicine. She moved to the United States to develop her career as a clinician-scientist and began her research studying the mechanisms linking obesity and Type 2 diabetes with breast cancer as a fellow in 2010. She graduated from fellowship in 2012 and was promoted to Assistant Professor in the Department of Medicine at Mount Sinai School of Medicine and given her own lab space to develop her research into cholesterol and breast cancer. She spends 80% of her time conducting research and the remaining 20% of her time treating endocrinology patients, many of who are also oncology patients, giving her first hand experience of the growing number of patients with obesity and Type 2 diabetes with cancer and the need to understand the links between metabolic conditions and cancer to appropriately treat these patients. Dr. Gallagher's goals during the K08 Award period are to develop her skills in a core set of molecular biology techniques; broaden her knowledge of cancer biology and lipidology; form collaborations for future research projects and advance our understanding of the mechanisms linking elevated cholesterol and breast cancer. Dr. Gallagher's mentors, Drs. LeRoith, Parsons, and Ginsberg, individually have many years of successful mentoring experience and are all experts in their own areas of research. In addition to her mentors, Dr. Gallagher has succeeded in putting together a team of advisors in the fields of oncology and metabolism from Mount Sinai and Columbia University who will provide their support in specific aspects of the current project, her career progression and the development of future basic science and clinical research projects based on the results of the experiments described in this proposal. Furthermore, Mount Sinai School of Medicine offers all of the environmental support Dr. Gallagher needs to succeed in her research and overall career objectives. The proposed research project aims to examine the mechanisms linking obesity, Type 2 diabetes and increased breast cancer risk, in order to identify targets for therapies that will improve survival in these women. Elevated serum cholesterol is frequently seen in people with obesity and Type 2 diabetes. These patients may have elevated low density lipoprotein (LDL) or very low density lipoprotein (VLDL). These abnormal elevations in serum cholesterol have been associated with an increased risk of hormone receptor negative and Her2 overexpressing breast cancers and a poor prognosis in breast cancer patients. It is hypothesized that increased cholesterol delivery to breast cancers by VLDL and/or LDL is driving breast cancer growth and spread, particularly in breast cancers with high levels of the low-density lipoprotein receptor (LDLR) that mediates cholesterol uptake from VLDL and LDL. This cholesterol uptake may promote tumor growth by activating signaling pathways that promote survival and proliferation. In addition, cholesterol may be metabolized into biologically active metabolites (one of which is 25-hydroxycholesterol) that may promote tumor metastasis. Therefore, the research hypothesis for this proposal is that elevated circulating cholesterol in the form of VLDL or LDL cholesterol promotes breast cancer growth and metastasis by delivery of cholesterol to cancer cells via the LDLR. The main aims of Dr. Gallagher's proposed research are: (1) To determine if high circulating cholesterol promotes breast cancer growth directly by increased cholesterol uptake through the LDLR in estrogen receptor positive, hormone receptor negative and Her2 overexpressing breast cancers; (2) To examine if cholesterol uptake through the LDLR leads to activation of a particular signaling pathway in all breast cancer subtypes and if lowering serum lipid levels and silencing the LDLR on tumor cells prevents activation of this pathway; (3) To determine the role of the cholesterol metabolite 25-hydroxycholesterol on tumor growth and metastasis by targeting the enzymes involved in its formation and studying the effects of 25- hydroxycholesterol on intracellular signaling, cytokine expression and epithelial-to-mesenchymal transition. Through these studies Dr. Gallagher aims to advance the field of metabolism and cancer by understanding the role of cholesterol in different breast cancer subtypes. With the results of these studies and through her collaborators and advisors, she plans to develop translational projects to change clinical practice and appropriately treat patients with obesity, Type 2 diabetes and breast cancer. Her abilities, dedication and determination to succeed in her goals are recognized by the Dean and Chair of Medicine at Mount Sinai School of Medicine, as well as her mentors and advisors, who are all offering their support to help her successfully complete her project and become an independent investigator and expert in the field of metabolism and cancer.

 描述(申请人提供)：这份K08临床科学家发展导师奖提案的目的是描述Emily Gallagher博士的五年培训、发展和导师计划，以及她的研究计划，以了解肥胖、2型糖尿病和乳腺癌之间的联系，特别是通过研究高循环胆固醇对乳腺癌进展的影响。加拉格尔博士以优异的成绩获得了爱尔兰都柏林大学学院的医学博士学位。在搬到纽约之前，她在爱尔兰接受了临床培训，并获得了内科和内分泌学董事会认证。作为一名临床医生，加拉格尔博士认识到基础科学研究在推动临床医学发展中的重要性。她移居美国，发展自己的临床科学家职业生涯，并于2010年以研究员身份开始研究肥胖和2型糖尿病与乳腺癌之间的联系机制。她于2012年毕业，并被提升为西奈山医学院医学系的助理教授，并给了自己的实验室空间来发展她对胆固醇和乳腺癌的研究。她80%的时间进行研究，其余20%的时间治疗内分泌科患者，其中许多人也是肿瘤科患者，这让她亲身体验到肥胖和2型糖尿病合并癌症的患者越来越多，以及需要了解代谢状况和癌症之间的联系才能适当地治疗这些患者。加拉格尔博士在K08颁奖期间的目标是发展她在一套核心分子生物学技术方面的技能；拓宽她在癌症生物学和血脂学方面的知识；为未来的研究项目形成合作，并增进我们对高胆固醇与乳腺癌之间的联系机制的理解。加拉格尔博士的导师勒罗思博士、帕森斯博士和金斯伯格博士各自都有多年成功的指导经验，都是各自研究领域的专家。除了她的导师，加拉格尔博士还成功地组建了一支来自西奈山和哥伦比亚大学的肿瘤学和新陈代谢领域的顾问团队，他们将在当前项目的具体方面、她的职业发展以及基于本提案中描述的实验结果的未来基础科学和临床研究项目的发展方面提供支持。此外，西奈山医学院为加拉格尔博士成功完成她的研究和总体职业目标提供了所有环境支持。这项拟议的研究项目旨在研究肥胖、2型糖尿病和乳腺癌风险增加之间的联系机制，以确定将提高这些女性存活率的治疗目标。血清胆固醇升高常见于肥胖症和2型糖尿病患者。这些患者可能有低密度脂蛋白(LDL)升高或极低密度脂蛋白(VLDL)升高。血清胆固醇的这些异常升高与激素受体阴性和Her2过度表达乳腺癌的风险增加以及乳腺癌患者的不良预后有关。据推测，极低密度脂蛋白和/或低密度脂蛋白增加对乳腺癌的胆固醇输送正在推动乳腺癌的生长和扩散，特别是在低密度脂蛋白受体(LDLR)水平高的乳腺癌中，低密度脂蛋白受体(LDLR)介导从极低密度脂蛋白和低密度脂蛋白中摄取胆固醇。这种胆固醇摄取可能通过激活促进生存和增殖的信号通路来促进肿瘤生长。此外，胆固醇可能被代谢成生物活性代谢物(其中之一是25-羟基胆固醇)，可能会促进肿瘤转移。因此，这一建议的研究假设是，循环中以极低密度脂蛋白或低密度脂蛋白胆固醇的形式升高的胆固醇通过将胆固醇输送到癌细胞来促进乳腺癌的生长和转移。加拉格尔博士提出的研究的主要目的是：(1)确定在雌激素受体阳性、激素受体阴性和Her2过表达的乳腺癌中，高循环胆固醇是否通过LDLR增加胆固醇摄取而直接促进乳腺癌的生长；(2)检查通过LDLR摄取胆固醇是否导致所有乳腺癌亚型中特定信号通路的激活，以及降低血脂水平和沉默肿瘤细胞上的LDLR是否阻止了这一途径的激活；(3)通过研究胆固醇代谢产物25-羟基胆固醇对细胞内信号转导、细胞因子表达及上皮细胞向间充质转化的影响，探讨其在肿瘤生长和转移中的作用。通过这些研究，加拉格尔博士的目标是通过了解胆固醇在不同乳腺癌亚型中的作用，推动新陈代谢和癌症领域的发展。根据这些研究的结果，并通过她的合作者和顾问，她计划开发翻译项目，以改变临床实践，并适当地治疗肥胖症、2型糖尿病和乳腺癌患者。她的能力、奉献精神和实现目标的决心得到了西奈山医学院院长和医学院主席以及她的导师和顾问的认可，他们都提供支持，帮助她成功完成项目，成为新陈代谢和癌症领域的独立研究员和专家。