ADAM12 in Breast Tumor Initiating Cells

乳腺肿瘤起始细胞中的 ADAM12

• 批准号: 8792604
• 负责人: Anna Zolkiewska
• 金额: $ 31.13万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792604
• 关键词: Accounting; Adverse effects; Biology; Breast Cancer Cell; Breast Epithelial Cells; Cell Surface Proteins; Cell surface; Cells; Cleaved cell; Clinical Data; Data; Detection; Diagnostics Research; Disintegrins; Down-Regulation; Epidermal Growth Factor; Estrogen receptor negative; Family; Goals; Health; Heterogeneity; In Vitro; Knowledge; Laboratories; Left; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Messenger RNA; Meta-Analysis; Metalloproteases; Methods; MicroRNAs; Molecular; Neoadjuvant Therapy; Neoplasm Metastasis; Normal tissue morphology; Outcome; Outcome Study; Pathway interactions; Patients; Pattern; Population; RNA Splicing; Radiation therapy; Reagent; Recurrence; Research; Residual Tumors; Resistance; Rest; Role; Signal Pathway; Signal Transduction; Surface; Testing; Time; Transforming Growth Factors; Translational Research; Up-Regulation; Variant; Work; autocrine; base; cancer cell; cancer therapy; chemotherapy; epithelial to mesenchymal transition; improved; in vivo; innovation; malignant breast neoplasm; member; new therapeutic target; notch protein; novel marker; outcome forecast; paracrine; self-renewal; stem; therapeutic target; tool; transcription factor; tumor; tumorigenic

DESCRIPTION (provided by applicant): Breast tumor initiating cells (BTICs), also referred to as cancer stem-like cells, drive breast tumor formation, recurrence, and metastasis. BTICs are largely resistant to chemotherapy and radiotherapy, posing a major obstacle to effective cancer treatment. Therefore, there is an urgent need to develop approaches that would not only destroy the existing BTICs, but would also detect and block the emergence of new BTICs. The long-term goal of our research is to understand how BTICs differ from the rest of breast tumor cells and how this knowledge can be used to develop new anti-BTICs strategies. The objective of this application is to evaluate ADAM12, a member of the ADAM family of cell-surface disintegrin-metalloproteases, as a novel marker and a novel therapeutic target in BTICs. Our central hypothesis is that ADAM12 is specifically induced in BTICs and, by modulating autocrine/paracrine cell signaling, it increases the formation, self-renewal, and/or tumorigenic potential of BTICs. To test our hypothesis, we will pursue the following Specific Aims: 1. Identify mechanisms responsible for the selective up-regulation ADAM12 expression in BTIC-enriched populations of cells. 2. Evaluate ADAM12 as a selective marker for BTICs. 3. Determine the role of ADAM12 in the biology of BTICs. Our studies are significant because they strive to produce new research and diagnostic tools for detection of BTICs and to develop new therapies to target BTICs, which are of critical importance to improve patient survival. The proposed research is innovative because for the first time it takes into account the molecular heterogeneity of breast tumors and new information on the expression pattern of ADAM12 in various molecular subtypes of breast cancer.

描述（由申请人提供）：乳腺肿瘤引发细胞（BTICS），也称为癌症干细胞，驱动乳腺肿瘤形成，复发和转移。 BTIC在很大程度上对化学疗法和放射疗法具有抗药性，这是有效癌症治疗的主要障碍。因此，迫切需要开发方法，不仅会破坏现有的BTIC，而且还将发现并阻止新的BTIC的出现。我们研究的长期目标是了解BTIC与乳腺肿瘤细胞的其余部分有何不同，以及如何使用这些知识来制定新的抗BTICS策略。该应用的目的是评估ADAM12（ADAM12），这是细胞表面分解蛋白 - 甲基甲蛋白酶的成员，作为BTICS中新型标记和新型治疗靶标。我们的中心假设是ADAM12是在BTIC中特异性诱导的，并且通过调节自分泌/旁分泌细胞信号传导，它增加了BTICS的形成，自我更新和/或肿瘤潜力。为了检验我们的假设，我们将追求以下特定目标：1。 负责在富含BTIC的细胞种群中选择性上调ADAM12表达的机制。 2。评估ADAM12作为BTIC的选择性标记。 3。确定ADAM12在BTIC生物学中的作用。我们的研究很重要，因为它们努力生产新的研究和诊断工具来检测BTIC，并开发新的疗法以靶向BTIC，这对于改善患者生存至关重要。拟议的研究具有创新性，因为它首次考虑了乳腺肿瘤的分子异质性以及有关乳腺癌各种分子亚型ADAM12表达模式的新信息。