ALPHA6/BETA4-INTEGRIN MEDIATED APOPTOSIS RESISTANCE

描述：(改编自研究人员的摘要)乳腺癌 耐药治疗经常在最初治疗数年后复发 疾病。根除这些顽固性癌症取决于对 抗死亡(DR)的起源和肿瘤的发生机制 休眠。我们已经展示了a)通过基底膜(BM)传递信号 整合素a3/b1和a6/b4诱导S-1人乳腺癌细胞株的研究 上皮细胞(S-1微血管内皮细胞)抑制生长并形成极化的腺泡，而 它们的恶性对应物(T4-2)不能抑制生长或形成极腺泡 作为对这些相同信号的响应，b)S-1微血管内皮细胞依赖于A3/b1-整合素 信号为生存，而在恶性转化(T4-2)后，它们 独立于b1-整合素信号，c)而不是死亡，抑制 B1整合素或表皮生长因子受体(EGFR)在这些细胞中的活性 T4-2微血管内皮细胞，诱导其生长停滞，形成极化的腺泡(表型 回复‘，T4-R)，并在’休眠‘状态下存活，以及d)这种’表型‘ 只有在存在可延展的BM的情况下才会发生回复，其中这些T4-2 MEC 同时接收正确的生化和空间信号，这使他们能够 交叉调节它们的黏附和生长因子受体。我们最近发现了e) S-1和T4-R微血管内皮细胞的极化腺泡均为DR。 不同的“诱导细胞凋亡”刺激。因此，我们得出了以下结论 假设：给出正确的生化和空间线索 细胞外基质(ECM)，肿瘤细胞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抵抗治疗。 经检测，S-1和T4-R MEC腺泡内皮细胞BM诱导的DR是 与a6/b4-整合素的结扎和组织极性有关。因此， 这些研究的目的是了解BM是如何诱导极化的DR的 MEC腺泡蛋白通过a6/b4-整合素。我们将使用HMT-3522型S-1非恶性和 T4-2肿瘤MEC模型、3DECM检测及细胞分子方法：1. 确定骨髓信号如何通过a6/b4-整合素、组织极性、腺泡 组织和灾难恢复是相关的。方法包括测试 A6/b4-整合素可以在无极性和三维腺泡的情况下指导DR 结构，如果不是，极性的程度或结构组织是什么 这是必要的。2.描述与以下各项相关的最小信令事件 A6/b4-整合素诱导的DR：操纵a6/b4-整合素 半桥粒组装和PI3K和Shc的胞内信号转导。 3.开展研究以阐明DR是如何通过以下途径在MEC中诱导的 A6/b4-整合素：检查P53状态与 A6/b4-整合素诱导的DR及细胞凋亡途径的确定 被封锁了。这些研究应该引导出合理的方法来开发替代方案 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.