ALPHA6/BETA4-INTEGRIN MEDIATED APOPTOSIS RESISTANCE

描述：（改编自研究者摘要） 对治疗的抵抗经常在最初的治疗后数年复发。 疾病根除这些恶性肿瘤取决于对 死亡抵抗（DR）的起源和肿瘤的机制 休眠我们已经显示了a）通过基底膜（BM）的信号传导 整合素a3/b1和a6/b4诱导S-1非恶性人HMT-3522乳腺癌 上皮细胞（S-1 MEC）生长停滞并形成极化腺泡，而 它们的恶性对应物（T4-2）不能生长停滞或形成极性腺泡 响应于这些相同的信号，B）S-1 MEC依赖于α 3/β 1-整联蛋白 生存信号，而恶性转化（T4-2）后， 变得不依赖于b1-整联蛋白信号传导，c）而不是死亡，抑制 这些细胞中的b1-整联蛋白或表皮生长因子受体（EGFR）活性 T4-2 MEC，诱导它们生长停滞，形成极化腺泡（“表型 回复“，T4-R），并在”休眠“状态下存活，以及d）这种”表型 “逆转”只发生在有延展性骨髓的情况下， 接收正确的生化和空间信号，这使他们能够 交叉调节它们的粘附和生长因子受体。最近发现e） S-1和T4-R MEC的极化腺泡都是DR， 不同的“诱发癫痫”刺激。因此，我们得出以下结论： 假设：在给定正确的生物化学和空间线索的情况下， 细胞外基质（ECM），肿瘤细胞的亚群存活并进入休眠状态 并通过利用特定的整合素连接途径来治疗。 经检查，我们发现BM诱导的DR在S-1和T4-R MEC腺泡中， 与α 6/β 4-整联蛋白的连接和组织极性相关。因此 这些研究的目的是了解BM如何在极化中诱导DR。 MEC腺泡通过α 6/β 4-整联蛋白。我们将使用HMT-3522 S-1非恶性肿瘤， T4-2肿瘤MEC模型，3D ECM测定以及细胞和分子方法：1. 确定BM如何通过α 6/β 4整合素、组织极性、腺泡 组织和DR是相关的。方法包括测试是否 α 6/β 4-整合素可以在缺乏极性和3D腺泡的情况下指导DR。 结构，如果不是，什么程度的极性或结构组织是 必要2.描绘出与之相关的最小信号事件， α 6/β 4-整联蛋白诱导的DR通过：操纵α 6/β 4-整联蛋白导向的 半桥粒装配和通过PI 3激酶和Shc的细胞内信号传导。 3.启动研究以阐明如何通过以下方式在MEC中诱导DR a6/b4-整合素通过：检查p53状态与 α 6/β 4-整联蛋白诱导的DR和确定凋亡途径的位置 被挡出.这些研究应导致合理的方法，以开发替代 治疗

DESCRIPTION: (Adapted from the investigator's abstract) Breast cancers that are resistant to therapy frequently recur years after treatment of the initial disease. Eradication of these recalcitrant cancers depends upon understanding the origins of death-resistance (DR), and the mechanisms underlying tumor dormancy. We have shown a) signaling through the basement membrane (BM) integrins a3/b1 and a6/b4 induces S-1 nonmalignant human HMT-3522 mammary epithelial cells (S-1 MECs) to growth-arrest and form polarized acini, whereas their malignant counterparts (T4-2) fail to growth-arrest or form polar acini in response to these same signals, b) S-1 MECs are dependent on a3/b1-integrin signaling for survival, whereas following malignant transformation (T4-2) they become independent of b1-integrin signaling, c) instead of dying, inhibition of either b1-integrin or epidermal growth factor receptor (EGFR) activity in these T4-2 MECs, induces them to growth-arrest, form polarized acini ('phenotypic reversion', T4-R), and survive in a 'dormant' state, and d) this 'phenotypic reversion' occurs only in the presence of a malleable BM, where these T4-2 MECs receive both the correct biochemical and spatial signals, which allow them to cross-modulate their adhesion and growth factor receptors. We recently found e) that the polarized acini of both S-1 and T4-R MECs are DR to a number of disparate 'apoptosis-inducing' stimuli. As such we have derived the following hypothesis: that given the correct biochemical and spatial cues from the extracellular matrix (ECM), subgroups of tumor cells survive to become dormant and recalcitrant to therapy by exploiting specific integrin-linked pathways. Upon examination we found the BM-induced DR in S-1 and T4-R MEC acini is associated with ligation of a6/b4-integrins and tissue polarity. Thus the objective of these studies is to understand how the BM induces DR in polarized MEC acini via a6/b4-integrins. We will use the HMT-3522 S-1 nonmalignant and T4-2 tumor MEC model, 3D ECM assays and cell and molecular approaches to: 1. Determine how BM signaling through a6/b4-integrins, tissue polarity, acini organization and DR are related. Approaches include testing whether a6/b4-integrins can direct DR in the absence of polarity and a 3D acinar structure, and if not, what degree of polarity or structural organization is necessary. 2. Delineate the minimal signaling events linked to a6/b4-integrin-induced DR by: manipulating a6/b4-integrin-directed hemidesmosome assembly and intracellular signaling through PI3kinase and Shc. 3. Initiate studies to elucidate how DR is induced in MECs through a6/b4-integrins by: examining the relationship between p53 status and a6/b4-integrin induced DR and determining where the apoptotic pathway is blocked. These studies should lead to rational approaches to develop alternate therapies.