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（由应用程序提供）：该K08指导的临床科学家发展奖的目的是描述Emily Gallagher博士的五年培训，发育和心理计划，除了她的研究计划外，还可以通过研究肥胖，2型糖尿病和乳腺癌之间的联系，特别是通过检查高循环胆固醇对乳腺癌乳腺癌进展的影响。加拉格尔博士获得了爱尔兰都柏林大学大学学院的荣誉医学博士学位。她在搬到纽约之前在爱尔兰接受了临床培训，并获得了内科和内分泌学的董事会认证。作为临床医生，Gallagher博士认识到基础科学研究在进行临床医学方面的重要性。她搬到美国发展了自己的临床科学家职业，并开始研究研究肥胖症和2型糖尿病与乳腺癌与乳腺癌相关的机制。她于2012年从研究生毕业，并晋升为医学院医学院医学院的助理教授，并为自己的实验室提供了自己的研究，并促进了自己的胆固醇和乳腺癌的研究。她花了80％的时间进行研究，其余20％的时间治疗内分泌学患者，许多人也是肿瘤学患者，这给了她第一手的肥胖症患者和癌症2型糖尿病的患者的第一手经验，并且需要了解代谢病和癌症之间的联系以适当治疗这些患者。 Gallagher博士在K08奖项期间的目标是通过一套核心分子生物学技术发展自己的技能。扩大了她对癌症生物学和脂质学的了解；为未来的研究项目形成合作，并促进我们对升高胆固醇和乳腺癌联系的机制的理解。 Gallagher博士的导师Leroith博士，Parsons和Ginsberg单独拥有多年的成功指导经验，并且都是他们自己的研究领域的专家。除了她的导师外，Gallagher博士还成功地组建了一群顾问团队，该团队在西奈山和哥伦比亚大学的肿瘤学和代谢领域，他们将在当前项目的特定方面，她的职业发展以及根据该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提供支持。此外，西奈山医学院提供了加拉格尔博士在她的研究和整体职业目标中取得成功所需的所有环境支持。拟议的研究项目旨在检查将肥胖，2型糖尿病和乳腺癌风险增加的机制，以确定可以改善这些女性生存的疗法的靶标。肥胖症和2型糖尿病患者经常看到升高的血清胆固醇。这些患者的低密度脂蛋白（LDL）或非常低密度脂蛋白（VLDL）的升高。血清胆固醇中的这些异常升高与马酮受体阴性和HER2过表达的乳腺癌的风险增加有关，并且对乳腺癌患者的预后不良。假设VLDL和/或LDL增加胆固醇向乳腺癌的递送增加了乳腺癌的生长并扩散，尤其是在低密度脂蛋白受体（LDLR）的乳腺癌中，可介导VLDL和LDL的胆固醇摄取。这种胆固醇摄取可以通过激活促进生存和增殖的信号通路来促进肿瘤的生长。此外，可以将胆固醇代谢为生物活性代谢产物（其中一种是25-羟基胆固醇），可以促进肿瘤转移。因此，该提议的研究假设是，以VLDL或LDL胆固醇形式升高循环胆固醇，通过通过LDLR将胆固醇递送到癌细胞中促进乳腺癌的生长和转移。 Gallagher博士提出的研究的主要目的是：（1）确定高循环胆固醇是否通过在雌激素受体阳性，马酮受体阴性中通过LDLR增加胆固醇的吸收来直接促进乳腺癌的生长，而HER2 HER2过表达乳腺癌； （2）检查通过LDLR吸收胆固醇是否会导致所有乳腺癌亚型中特定信号通路的激活，以及是否降低血清脂质水平并使肿瘤细胞上的LDLR沉默，以防止这种途径激活该途径； （3）通过靶向涉及其形成的酶并研究25-羟基胆固醇对25-羟基胆固醇对细胞内信号，细胞因子表达，上皮 - 间质质体的影响的影响，确定胆固醇代谢产物25-羟基胆固醇对肿瘤生长和转移的作用。通过这些研究，Gallagher博士的目的是通过了解胆固醇在不同乳腺癌亚型中的作用来推动代谢和癌症的领域。通过这些研究的结果以及通过其合作者和顾问，她计划开发转化项目以改变临床实践，并适当治疗肥胖症，2型糖尿病和乳腺癌的患者。她的能力，奉献精神和决心取得成功的目标得到了西奈山医学院的院长和医学主席，以及她的导师和顾问，他们都提供支持，以帮助她成功完成她的项目，并成为代谢和癌症领域的独立研究员和专家。