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

降低患三阴性乳腺癌 (TNBC) 的风险

• 批准号: 8761399
• 负责人: Coral Oghenerukevwe Omene
• 金额: $ 15.5万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-23 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761399
• 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; MDA MB 231; 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

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，使用这个有指导的临床科学家职业发展奖，是为了在分子肿瘤学方面取得专业知识，这样我就可以成为乳腺癌研究的独立研究员。我长期致力于内科肿瘤学领域的翻译性、以患者为中心的研究和治疗，我的临床和研究培训证明了这一点。我的职业重点是将基本的科学概念转化为对正在接受乳腺癌治疗的患者的实际改进。我特别感兴趣的是，通过了解这种疾病的生物学和病因学，为三阴性乳腺癌(TNBC)患者开发创新的治疗方法。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，我一直对缺乏合理的TNBC疗法感到沮丧，因此见证了成功治疗TNBC患者的困难。正是由于无法有效治疗TNBC，我在过去两年半的时间里一直与K.Frenkel博士合作进行研究，调查咖啡酸苯乙酯(CAPE)的各种抗肿瘤作用。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，数千年来一直安全使用。我已发表的工作表明，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的模型)(Jing W，Omene C，2011)。重要的是，CAPE抑制了MDA-231 TNBC干细胞，从而降低了肿瘤形成潜力(Omene C，2011)。通过与OAO‘Connor博士的合作，我们发现CAPE的这些抗肿瘤作用在一定程度上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，并在表观遗传学上导致以前沉默的雌激素受体(ER)基因在MDA-231 TNBC细胞中重新表达。这个项目为我提供了一个独特的机会来研究TNBC的发展，并试图利用我的这一奖项的导师巴塞洛斯-霍夫博士建立的一个新的TNBC小鼠模型，来修正CAPE发展它的风险。在这种放射嵌合体模型中，将致癌基因Trp53缺失的乳腺上皮移植到受照射的宿主身上，显示出侵袭性肿瘤的加速发展，其分子特征与未受照射的宿主中发生的肿瘤不同。在受辐射的宿主中发生的肿瘤主要是雌激素受体阴性的，这与乳腺干细胞(MASC)的去调节有关。这一模型将使我能够将我使用CAPE和对TNBC的兴趣的工作数据结合在一起，以测试CAPE是否可以用来修正发展TNBC的风险。我们假设在这种TNBC模型中，由于其新型的HDAC抑制剂特性，CAPE将达到预防癌症发展的目的。我们计划：1)确定CAPE是否影响受照射小鼠的肿瘤潜伏期和/或肿瘤类型，2)确定CAPE是否修改从受照射小鼠分离的乳腺干细胞库，以及3)评估CAPE作为组蛋白脱乙酰酶抑制剂在受照射细胞中的作用。这项研究将对我们理解跨国公司的发展具有重要意义。对于TNBC的高危人群，它有可能在临床环境中作为化学预防很容易被翻译。此外，TNBC患者的治疗选择有限，而CAPE用作化学预防可能会影响这些女性的预后。我有信心，在我迈向成为一名独立调查员的过程中，能够实现这项提案中概述的目标，因为我拥有广泛的可用资源。他们包括一位杰出的研究人员作为导师，大量的教育机会，良好的机构环境，共享的核心设施和许多随时可以分享他们的专业知识的专家关键教员。好了！