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

描述（由申请人提供）：我的目标，使用这个指导临床科学家职业发展奖，是实现分子肿瘤学的专业知识，使我可以成为一个独立的研究人员在乳腺癌研究。我长期致力于医学肿瘤学领域的转化，以患者为导向的研究和治疗，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科学概念转化为乳腺癌（BC）患者的实际改善。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（HER 2+）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，因此目睹了成功治疗TNBC患者的困难。正是因为无法有效治疗TNBC，我在过去的2.5年里与K博士一起进行了研究。研究咖啡酸苯乙酯（CAPE）的多种抗肿瘤作用。CAPE是蜂蜜的主要生物活性成分，蜂蜜是蜜蜂收集的天然产品，数千年来一直安全使用。我已发表的工作表明，CAPE通过细胞周期阻滞、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）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奥康纳博士的合作，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，未发表）。例如，CAPE暴露导致EGFR过表达减少，这是TNBC增殖的关键驱动因素，而表观遗传学导致先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，并试图通过CAPE修改其发展的风险，使用由我的导师Dr. Dallos-Hoff建立的TNBC新小鼠模型。这种辐射嵌合体模型，其中受辐射的宿主移植有致癌的Trp 53缺失乳腺上皮，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。在受照射的宿主中产生的肿瘤主要是雌激素受体阴性的，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是否可以用来改变发展TNBC的风险。我们假设，由于CAPE的新型HDAC抑制剂特性，该TNBC模型中癌症发展的预防将通过CAPE实现。我们计划：1）确定CAPE是否影响辐照小鼠中的肿瘤潜伏期和/或肿瘤类型，2）确定CAPE是否修饰从辐照小鼠分离的乳腺干细胞库，和3）评估CAPE作为辐照细胞中组蛋白脱乙酰酶抑制剂的作用。这项研究将大大有助于我们对TNBC发展的理解。它有可能在临床环境中很容易转化为TNBC高风险人群的化学预防。此外，TNBC患者的治疗选择有限，CAPE用作化学预防可能会影响这些女性的预后。我有信心，我可以完成这个建议中所列的目标，因为我朝着成为一个独立的调查员提供了广泛的资源给我。它们包括一个杰出的研究人员作为导师，众多的教育机会，一个优秀的机构环境，共享的核心设施和许多专家关键教师随时可以分享他们的专业知识。

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.