Investigation of the Role of NF-??B in Breast Cancer Tumor Initiating Cells

NF-κB在乳腺癌肿瘤起始细胞中作用的研究

• 批准号: 7995626
• 负责人: Megan F Kendellen
• 金额: $ 1.51万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7995626
• 关键词: Biology; Breast Cancer Cell; Breast Cancer Treatment; Cancer cell line; Cell physiology; Cells; Cellular biology; Characteristics; Data; Development; ERBB2 gene; Exhibits; Gene Targeting; Generations; Human; In Vitro; Investigation; Link; MAP3K7 gene; Malignant Neoplasms; Mammary Neoplasms; Modeling; Mus; NF-kappa B; NFKB Signaling Pathway; Neoplasm Metastasis; Patients; Phenotype; Play; Population Heterogeneity; Primary Neoplasm; Protein Family; Protein Kinase; Radiation; Resistance; Role; Sampling; Signal Transduction; Stem cells; Testing; Work; cancer cell; cell motility; epithelial to mesenchymal transition; in vivo; malignant breast neoplasm; neoplastic cell; novel; public health relevance; self-renewal; therapy resistant; tumor; tumor initiation

DESCRIPTION (provided by applicant): Among the heterogeneous population of cells in a tumor is a subset of cells that share characteristics with stem cells and which are termed tumor initiating cells (TICs). TICs exhibit a robust capacity to self-renew and thus play a significant role in tumor initiation. They also exhibit high metastatic potential in vivo, which is manifested in vitro as high motility and invasiveness. Notably, TICs are also resistant to radiation and many currently available chemotherapeutics. Thus, TICs are a novel and therapeutically powerful anti-cancer target. However, little is known their biology, which has hindered the development of TIC-specific chemotherapeutics. We hypothesize that the NF-kB signaling pathway is required for the TIC phenotype in breast cancer cells. This model is supported by data that inhibition of NF-kB in some contexts results in a reduction in cellular self-renewal and NF-kB is involved in the only cellular process to be linked to the generation of TICs, the epithelial-to-mesenchymal transition (EMT). In this proposal, we will test whether NF-kB signaling is preferentially activated in breast cancer TICs and is required for the TIC phenotype in primary human breast tumor samples, human breast cancer cell lines, and murine models of human HER2+ and basal breast cancer. Given the potential association of NF-kB and EMT in TICs, we will also investigate the hypothesis that at least part of the role of NF-kB in TICs is the stimulation of EMT. Finally, we will investigate whether a signaling cascade that depends on the protein kinase TAK1 regulates NF-kB activity in TICs and determine which NF-kB target genes are important for the TIC phenotype. We anticipate that these studies will facilitate the identification of novel chemotherapeutic targets for the treatment of breast cancer. PUBLIC HEALTH RELEVANCE: Breast tumors are thought to contain a sub-set of cancer cells termed tumor initiating cells (TICs) that are responsible for the establishment of primary tumors and promoting metastasis and which are especially resistant to the therapies currently available to patients. Little is currently known about TIC biology, but recent evidence suggests that the NF-kB family of proteins may be important. As such, work in this study to delineate the role of NF-kB in TICs, how NF-kB is regulated in such cells, and how NF-kB promotes the TIC phenotype will facilitate the development of novel chemotherapeutics for breast cancer.

描述(由申请人提供)：在肿瘤中不同种类的细胞中，有一部分细胞与干细胞具有相同的特征，被称为肿瘤起始细胞(TICs)。抽搐表现出强大的自我更新能力，因此在肿瘤的发生中起着重要作用。它们在体内也表现出高转移潜能，在体外表现为高移动性和侵袭性。值得注意的是，抽搐也对辐射和许多目前可用的化疗药物具有抵抗力。因此，抽搐是一种新颖的、具有强大治疗作用的抗癌靶点。然而，对它们的生物学特性知之甚少，这阻碍了TIC特异性化疗药物的发展。我们假设核因子-kB信号通路是乳腺癌细胞TIC表型所必需的。这一模型得到了以下数据的支持：在某些情况下，抑制核因子-kB会导致细胞自我更新的减少，并且核因子-kB参与了唯一与抽动的产生有关的细胞过程，即上皮到间充质的转变(EMT)。在这项研究中，我们将测试核因子-kB信号是否在乳腺癌痉挛中优先被激活，并在原发人类乳腺肿瘤样本、人乳腺癌细胞系以及人HER2+和基底乳腺癌的小鼠模型中是TIC表型所必需的。鉴于核因子-kB与肌动过速在抽动中的潜在关联，我们还将探讨核因子-kB在抽动中至少部分作用于肌动过速刺激的假说。最后，我们将研究依赖于蛋白激酶TAK1的信号级联是否调节TIC中的核因子-kB活性，并确定哪些核因子-kB靶基因对TIC表型重要。我们预计，这些研究将有助于确定乳腺癌治疗的新化疗靶点。 与公共卫生相关：乳腺肿瘤被认为含有一种称为肿瘤起始细胞(TICS)的癌细胞亚群，负责建立原发肿瘤并促进转移，而且对目前患者可用的治疗方法特别耐药。目前对TIC生物学知之甚少，但最近的证据表明，核因子-kB蛋白家族可能是重要的。因此，本研究旨在阐明核因子-kB在TICs中的作用、核因子-kB是如何在TICs细胞中被调控的、以及核因子-kB是如何促进TIC表型的，这将有助于乳腺癌新化疗药物的开发。