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

描述（由申请人提供）：在肿瘤中的异质细胞群中，有一个细胞亚群与干细胞具有相同的特征，称为肿瘤起始细胞（TIC）。TIC表现出强大的自我更新能力，因此在肿瘤发生中发挥重要作用。它们在体内也表现出高转移潜力，这在体外表现为高运动性和侵袭性。值得注意的是，TIC还对辐射和许多目前可用的化疗药物具有抗性。因此，TIC是一种新的和治疗上有效的抗癌靶点。然而，对它们的生物学知之甚少，这阻碍了TIC特异性化疗药物的发展。 我们假设NF-kB信号通路是乳腺癌细胞中TIC表型所必需的。该模型得到以下数据的支持：在某些情况下抑制NF-kB导致细胞自我更新减少，并且NF-kB参与与TIC产生相关的唯一细胞过程，即上皮向间充质转化（EMT）。在本提案中，我们将测试NF-kB信号传导是否在乳腺癌TIC中优先激活，以及是否是原发性人乳腺肿瘤样本、人乳腺癌细胞系和人HER 2+和基底乳腺癌小鼠模型中TIC表型所需的。鉴于NF-kB和EMT在TIC中的潜在关联，我们还将研究NF-kB在TIC中至少部分作用是刺激EMT的假设。最后，我们将研究是否依赖于蛋白激酶TAK 1的信号级联调节TIC中的NF-κ B活性，并确定哪些NF-κ B靶基因对TIC表型很重要。我们预计，这些研究将有助于确定新的化疗靶点治疗乳腺癌。 公共卫生相关性：乳腺肿瘤被认为含有一组称为肿瘤起始细胞（TICs）的癌细胞亚群，它们负责建立原发性肿瘤并促进转移，并且对患者目前可用的疗法特别耐药。目前对TIC生物学知之甚少，但最近的证据表明NF-kB蛋白家族可能很重要。因此，这项研究中的工作描绘了NF-kB在TIC中的作用，NF-kB在这些细胞中如何调节，以及NF-kB如何促进TIC表型将促进乳腺癌新化疗药物的开发。

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.