Development of a novel targeted-therapy for treatment of basal-like breast cancer

描述（由申请人提供）：乳腺癌是美国女性中最常见的癌症。值得注意的是，绝经前非裔美国妇女的乳腺癌发病率明显高于白种人美国人，而且在任何年龄段的死亡率都更高。报告显示年轻的非裔美国患者基底样“三阴性”乳腺癌的发病率更高。目前，对于这种高度侵袭性的癌症，还没有有效的分子疗法，因此，患者的存活率很低。这项研究的主要意义在于它专注于识别和测试治疗这种侵袭性基底样乳腺癌的新的转化靶点。先前的研究表明，CD44高表达是基底样乳腺癌中干细胞样异种移植物启动细胞的关键组成部分；因此，确定CD44在这些肿瘤启动细胞中的作用是开发靶向治疗的重要一步。初步结果显示，与腔型乳腺癌亚型相比，基底样乳腺癌中CD44和独特的CD44变异表达上调。此外，初步研究已经确定了一种通常与哺乳动物肠道疾病相关的新型外毒素，它选择性地结合高CD44表达的乳腺癌细胞，改变CD44信号并诱导细胞死亡。因此，本研究旨在从功能上确定这种毒素与CD44相互作用的机制，并确定其作为治疗高CD44表达的基底样乳腺癌的潜力。在本提案的第一阶段，CD44的总水平和变异表达谱将在细胞系和原发性乳腺癌样本中使用绝对定量RT-PCR，流式细胞术和免疫组织化学来定义管腔和基底样乳腺癌表型。这些信息将用于确定毒素的靶细胞群，并将癌细胞对毒素暴露的敏感性与CD44表达和癌症表型相关联（目的1）。本研究的第二阶段提出了用于癌症治疗的毒素翻译开发所需的初始体内异种移植实验（目的2）。从该提案中产生的数据将为未来的提案提供基础，其总体目标是开发新的靶向疗法来治疗侵袭性基底样乳腺癌，特别是年轻的非裔美国女性。

DESCRIPTION (provided by applicant): Breast cancer is the most commonly diagnosed cancer in US women. Notably, premenopausal African- American women have a significantly higher incidence rate of breast cancer compared to Caucasian- American, and a higher mortality rate at any age. Reports show young African-American patients have a higher incidence of the basal-like "triple-negative" breast cancer. Currently, no effective molecular therapies exist for this highly aggressive cancer and, consequently, patient survival is poor. The primary significance of the proposed study is its focus on identifying and testing novel translational targets for treatment of this aggressive, basal-like breast cancer. Previous studies show high CD44 expression is a critical component of stem-like, xenograft-initiating cells in basal-like breast cancer; therefore, defining the role of CD44 in these tumor-initiating cells is a essential step in developing targeted therapeutics. Preliminary results show an upregulation of CD44, and unique CD44 variant expression, in basal-like breast cancer compared to luminal breast cancer subtypes. Additionally, preliminary studies have identified a novel exotoxin, commonly associated with enteric diseases of mammals, that selectively binds high CD44 expressing breast cancer cells, alters CD44 signaling and induces cell death. Therefore, this proposal intends to functionally determine the mechanisms of this toxin's interaction with CD44 and to determine its potential as a therapy for high CD44 expressing, basal-like breast cancer. During the first phase of this proposal, the total levels and variant expression profile of CD44 wil be defined in luminal and basal-like breast cancer phenotypes using absolute quantitative RT-PCR, flow cytometry and immunohistochemistry in cell lines and primary breast cancer samples. This information will be used to define the toxin's target population of cells, and correlate the sensitivity of cancer cells to toxin exposure with CD44 expression and cancer phenotypes (Aim 1). The second phase of this study proposes the initial in vivo xenograft experiments necessary for translational development of the toxin for cancer therapeutics (Aim 2). The data generated from this proposal will provide the foundation of future proposals with the overall goal to develop novel targeted therapies for treatment of aggressive, basal-like breast cancer, particularly in young African-American women.