Modifying The Risk For Developing Triple Negative Breast Cancer (TNBC)

降低患三阴性乳腺癌 (TNBC) 的风险

基本信息

批准号：
8544449
负责人：
Coral Oghenerukevwe Omene
金额：
$ 17.23万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8544449
关键词：
Acetylation Affect African American Angiogenesis Inhibition Award Basic Science Biological Factors Biology Breast Breast Cancer Cell Breast Cancer Model Breast Cancer Prevention Cancer Patient Cell Cycle Arrest Cells Chemoprevention Clinical Clinical Research Collaborations Core Facility Data Development Disease ERBB2 gene Environment Epidermal Growth Factor Receptor Epithelium Estrogen Receptors Estrogen receptor negative Etiology Exhibits Faculty Goals Growth Factor High Prevalence Histone Deacetylase Inhibitor Histones Hormone Receptor Human In Vitro Inhibition of Apoptosis K-Series Research Career Programs Ligands Link Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Measures Medical Oncology Mentors Modeling Molecular Molecular Profiling Morphogenesis Mus New Agents Oncogenic Patients Peripheral Blood Mononuclear Cell Population Prevention Protocols Progesterone Receptor Status Progesterone Receptors Property Propolis Publishing Radiation Radiation Chimera Receptor Gene Reporting Research Research Personnel Research Training Resources Risk Role Scientist Signal Transduction Stem cells Testing Time Transducers Translating Translations Transplantation Tumor Suppression Woman Work anticancer research caffeic acid phenethyl ester cancer cell cancer prevention cancer stem cell career chromatin remodeling high risk in vivo innovation interest irradiation jagged1 protein malignant breast neoplasm mammary epithelium member molecular oncology mortality mouse model notch protein novel outcome forecast overexpression patient oriented research progesterone receptor negative treatment effect triple-negative invasive breast carcinoma tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): My goal, using this Mentored Clinical Scientist Career Development Award, is to achieve expertise in Molecular Oncology so that I may become an independent investigator in Breast Cancer Research. I have had a long- standing commitment to translational, patient-oriented research and treatment in the field of medical oncology, as evidenced by my clinical and research training. My career focus is the translation of basic science concepts into practical improvements for patients being treated for breast cancer (BC). I am particularly interested in developing innovative treatments for patients with triple negative breast cancer (TNBC) by understanding both the biology and etiology of this disease. Unlike the targeted therapies identified by basic science to successfully treat hormone receptor (ER+/PR+) and growth factor (HER2+) overexpressing breast cancer, I have been frustrated by the lack of rational therapies for TNBC and as a result have witnessed the difficulty in successfully treating patients with TNBC. It is because of the inability to effectively treat TNBC that I have performed research for the past 2.5 years working with Dr. K. Frenkel, investigating the diverse anti-tumor effects of caffeic acid phenethyl ester (CAPE). CAPE is a major bioactive component of propolis, a natural product gathered by honeybees and used safely for millennia. My published work has shown that CAPE inhibits breast cancer cells, including MDA-MB-231 (MDA-231, a model for TNBC) breast tumor growth in vitro as well as in vivo via cell cycle arrest, apoptosis and inhibition of angiogenesis (Jing W, Omene C, 2011). Importantly, CAPE inhibits MDA-231 TNBC stem cells with a subsequent decrease in tumor-forming potential (Omene C, 2011). We found through the collaboration with Dr. OA O'Connor that these anti-tumor effects of CAPE are related in part to its role as a histone deacetylase (HDAC) inhibitor (Omene C et al, unpublished). For example, CAPE exposure leads to a decrease in EGFR over-expression, a key driver in the proliferation of TNBC, and epigenetically, causes the re-expression of a previously silenced estrogen receptor (ER) gene in MDA- 231 TNBC cells. This project offers me a unique opportunity to study the development of TNBC and attempt to modify the risk of its development by CAPE, using a new mouse model of TNBC established by Dr. Barcellos-Hoff, my mentor for this award. This radiation chimera model in which an irradiated host is transplanted with oncogenic Trp53 null mammary epithelium exhibits an accelerated development of aggressive tumors whose molecular signatures are distinct from tumors arising in non-irradiated hosts. Tumors arising in the irradiated host are predominantly estrogen receptor negative and this was linked to mammary stem cell (MaSC) deregulation. This model will allow me to meld together data from my work using CAPE and interest in TNBC to test whether CAPE can be used to modify the risk of developing TNBC. We hypothesize that prevention of cancer development in this TNBC model will be achieved by CAPE due to its novel HDAC inhibitor properties. We plan to: 1) Establish whether CAPE affects tumor latency and/or tumor type in irradiated mice, 2) Determine whether CAPE modifies the mammary stem cell pool isolated from irradiated mice and 3) Assess the effect of CAPE action as an inhibitor of histone deacetylase in irradiated cells. This research will significantly contribute to our understanding of TNBC development. It has the potential to be readily translatable as chemoprevention in the clinical setting for populations at high risk for TNBC. In addition, TNBC patients have limited treatment options and CAPE used as chemoprevention could impact on the prognosis of these women. I am confident that I can accomplish the goals as outlined in this proposal as I move toward becoming an independent investigator given the wide array of resources available to me. They include an outstanding researcher as a mentor, a multitude of educational opportunities, an excellent institutional environment, shared core facilities and many expert key faculty members readily available to share their expertise. !

描述（由申请人提供）：我的目标是利用指导临床科学家职业发展奖获得分子肿瘤学方面的专业知识，以便我可以成为乳腺癌研究的独立研究者。我长期致力于肿瘤内科领域的转化性、以患者为导向的研究和治疗，我的临床和研究培训就证明了这一点。我的职业重点是将基础科学概念转化为乳腺癌 (BC) 治疗患者的实际改进。我对通过了解三阴性乳腺癌 (TNBC) 的生物学和病因学来开发创新疗法特别感兴趣。与基础科学确定的成功治疗激素受体（ER+/PR+）和生长因子（HER2+）过表达乳腺癌的靶向疗法不同，我对 TNBC 缺乏合理的治疗方法感到沮丧，并因此目睹了成功治疗的困难。治疗 TNBC 患者。正是由于无法有效治疗 TNBC，我在过去 2.5 年里与 K. Frenkel 博士合作进行了研究，研究咖啡酸苯乙酯 (CAPE) 的多种抗肿瘤作用。 CAPE 是蜂胶的主要生物活性成分，蜂胶是蜜蜂采集的天然产品，安全使用了数千年。我发表的研究表明，CAPE 通过细胞周期停滞、细胞凋亡和抑制血管生成，在体外和体内抑制乳腺癌细胞，包括 MDA-MB-231（MDA-231，TNBC 模型）乳腺肿瘤生长（Jing W、Omene C，2011）。重要的是，CAPE 抑制 MDA-231 TNBC 干细胞，随后降低肿瘤形成潜力（Omene C，2011）。通过与 OA O'Connor 博士的合作，我们发现 CAPE 的这些抗肿瘤作用部分与其作为组蛋白脱乙酰酶 (HDAC) 抑制剂的作用有关（Omene C 等人，未发表）。例如，CAPE 暴露会导致 EGFR 过度表达减少，EGFR 过度表达是 TNBC 增殖的关键驱动因素，并且在表观遗传学上导致 MDA-231 TNBC 细胞中先前沉默的雌激素受体 (ER) 基因重新表达。这个项目为我提供了一个独特的机会来研究 TNBC 的发展，并尝试通过 CAPE 来改变其发展的风险，使用由我的导师 Barcellos-Hoff 博士建立的新 TNBC 小鼠模型。这种辐射嵌合体模型中，将致癌的Trp53乳腺上皮移植到受辐射的宿主中，表现出侵袭性肿瘤的加速发展，其分子特征与未受辐射的宿主中产生的肿瘤不同。受辐射宿主中产生的肿瘤主要是雌激素受体阴性，这与乳腺干细胞（MaSC）失调有关。这个模型将使我能够将我使用 CAPE 的工作数据和对 TNBC 的兴趣融合在一起，以测试 CAPE 是否可以用于降低发展 TNBC 的风险。我们假设，由于 CAPE 具有新颖的 HDAC 抑制剂特性，可以预防该 TNBC 模型中的癌症发展。我们计划：1) 确定 CAPE 是否影响受辐射小鼠的肿瘤潜伏期和/或肿瘤类型，2) 确定 CAPE 是否改变从受辐射小鼠中分离出的乳腺干细胞库，3) 评估 CAPE 作为组蛋白抑制剂的作用受辐射细胞中的脱乙酰酶。这项研究将极大地有助于我们了解 TNBC 的发展。它有可能很容易转化为临床环境中对 TNBC 高危人群的化学预防。此外，TNBC 患者的治疗选择有限，CAPE 作为化学预防可能会影响这些女性的预后。鉴于我拥有广泛的可用资源，我有信心在成为一名独立调查员的过程中能够实现本提案中概述的目标。其中包括作为导师的杰出研究人员、大量的教育机会、优良的机构环境、共享的核心设施以及许多随时可以分享其专业知识的专家骨干教师。！