ADAM12 in Breast Tumor Initiating Cells

描述（由申请人提供）：乳腺肿瘤起始细胞（Breast tumor initiation cells, BTICs），也被称为肿瘤干细胞样细胞，驱动乳腺肿瘤的形成、复发和转移。btic在很大程度上对化疗和放疗具有耐药性，这是有效治疗癌症的主要障碍。因此，迫切需要开发一种方法，不仅可以摧毁现有的btic，还可以检测和阻止新btic的出现。我们研究的长期目标是了解BTICs与其他乳腺肿瘤细胞的不同之处，以及如何利用这些知识开发新的抗BTICs策略。本申请的目的是评估ADAM12作为细胞表面分解素金属蛋白酶ADAM家族的成员，作为btic的新标记物和新治疗靶点。我们的中心假设是ADAM12在btic中被特异性诱导，并通过调节自分泌/旁分泌细胞信号传导，增加btic的形成、自我更新和/或致瘤潜力。为了验证我们的假设，我们将追求以下具体目标：1。识别

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.