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: 9274919
• 负责人: Coral Oghenerukevwe Omene
• 金额: $ 17.23万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9274919
• 关键词: Acetylation; Affect; African American; Angiogenesis Inhibition; Apoptosis; Award; Basic Science; Biology; Breast Cancer Cell; Cancer Model; Cancer Patient; Cell Cycle Arrest; Cells; Chemoprevention; Clinical; Clinical Research; Collaborations; Core Facility; Data; Development; Disease; ERBB2 gene; Environment; Epidermal Growth Factor Receptor; Epigenetic Process; Epithelium; Estrogen Receptors; Estrogen receptor negative; Etiology; Exhibits; Faculty; Goals; Growth Factor; HDAC4 gene; High Prevalence; Histone Deacetylase Inhibitor; Histones; Hormone Receptor; Human; In Vitro; 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; Natural Products; 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; antitumor effect; beta catenin; caffeic acid phenethyl ester; cancer cell; cancer prevention; cancer stem cell; career; chromatin remodeling; high risk; in vivo; innovation; interest; irradiation; malignant breast neoplasm; mammary epithelium; member; molecular oncology; mortality; mouse model; notch protein; novel; outcome forecast; overexpression; patient oriented research; progesterone receptor negative; targeted treatment; 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）：我的目标是使用这一指导的临床科学家职业发展奖，是为了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。我对医学肿瘤学领域的转化，以患者为导向的研究和治疗做出了长期的承诺，这是我的临床和研究培训所证明的。我的职业重点是将基础科学概念转化为接受乳腺癌治疗（BC）的患者的实际改进。我特别感兴趣地通过了解该疾病的生物学和病因来为三重阴性乳腺癌（TNBC）患者开发创新治疗。与基础科学确定的靶向疗法成功治疗激素受体（ER+/PR+）和生长因子（HER2+）过表达的乳腺癌，我对TNBC缺乏理性疗法感到沮丧，因此我见证了成功的困难治疗TNBC患者。由于无法有效治疗TNBC，我在过去的2。5年中与K. Frenkel博士进行了研究，研究了咖啡酸苯乙酯（CAPE）的不同抗肿瘤作用。开普（Cape）是蜂胶的主要生物活性成分，蜂巢是由蜜蜂收集的自然产物，并安全地用于数千年。我发表的工作表明，CAPE抑制了乳腺癌细胞，包括MDA-MB-231（MDA-231，TNBC模型）乳腺肿瘤在体外的生长以及通过细胞周期停滞，血管生成的凋亡和血管生成的抑制（JING）的体内生长（jing） W，Omene C，2011年）。重要的是，Cape抑制MDA-231 TNBC干细胞，随后肿瘤形成潜力降低（Omene C，2011）。我们通过与Oa O'Connor博士的合作发现，CAPE的这些抗肿瘤作用部分与其作为组蛋白脱乙酰基酶（HDAC）抑制剂的作用有关（Omene C等人，未发表）。例如，CAPE暴露导致EGFR过表达的降低，TNBC增殖的关键驱动力以及表观遗传的驱动因素会导致MDA-231 TNBC细胞中先前沉默的雌激素受体（ER）基因的重新表达。该项目为我提供了一个独特的机会，可以使用由我的奖项的导师Barcellos-Hoff博士建立的新的TNBC鼠标模型来研究TNBC的开发，并试图修改CAPE开发的风险。这种辐射嵌合体模型，其中辐射的宿主用致癌的TRP53无效乳腺上皮移植，表现出侵袭性肿瘤的加速发展，其分子特征与非辐照宿主的肿瘤不同。在辐照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。该模型将使我使用CAPE和对TNBC的兴趣将工作中的数据融合在一起，以测试CAPE是否可以用于修改开发TNBC的风险。我们假设在TNBC模型中预防癌症的发展，CAPE将由于其新颖的HDAC抑制剂特性而实现。我们计划：1）确定斗篷是否影响辐照小鼠中的肿瘤潜伏期和/或肿瘤类型，2）确定斗篷是否修改了从辐照小鼠中分离的乳腺干细胞池，3）评估Cape作用作为组蛋白抑制剂的效果辐照细胞中的脱乙酰基酶。这项研究将有助于我们对TNBC发展的理解。它有可能在临床环境中很容易被翻译为TNBC高风险的临床环境。此外，TNBC患者的治疗选择有限，并且用作化学预防的斗篷可能会影响这些妇女的预后。我有信心，鉴于我可以使用的广泛资源，我可以实现该提案中概述的目标。其中包括一位杰出的研究人员，作为导师，多种教育机会，出色的机构环境，共享的核心设施以及许多专家主要的教师，可以随时可用来分享他们的专业知识。