Mechanisms of breast cancer cell growth & tumorigenicity

描述(申请人提供)：越来越多的证据表明，适配蛋白p130Cas(Cas)在乳腺肿瘤中表达的变化可能导致癌症进展和不良预后。在人类乳腺肿瘤中，Cas的过度表达与复发的高概率和对抗雌激素他莫昔芬的内在耐药的高发生率相关。在过度表达Cas或其结合伙伴和-34/BCAR3的培养的乳腺癌细胞中，抗雌激素耐药性也很明显。CAS由多个结构域组成，每个结构域都有能力与不同的蛋白质阵列相互作用，从而促进潜在的不同功能结果。我们假设，Cas或And-34的过表达通过与这些蛋白的特定亚集相互作用激活信号通路，最终导致抗雌激素抵抗和细胞生理变化，这些变化与侵袭性肿瘤行为和不良预后相关。这一假说将在目标1中通过识别促进抗雌激素抵抗的Cas和-34的结构域和下游效应器来验证，并研究这些途径如何在这一过程中与雌激素受体功能协调或覆盖。在目标2中，我们将测试作为早期乳腺癌模型的细胞中Cas的过度表达是否可以诱导细胞生理和形态的变化，这些变化与获得更具侵袭性的生长和侵袭表型相一致。相反，我们还将测试作为晚期乳腺癌模型的细胞中Cas表达或功能的抑制是否逆转了这些细胞表现出的一些有害表型。已知的与上述研究中涉及的结构域结合的蛋白质的潜在功能贡献将在两个特定目标的背景下进行探索。然而，在那些涉及没有已知结合伙伴的结构域的情况下，或者当没有已知的结合蛋白被发现发挥作用时，将在目标3中尝试识别更多的结合伙伴并测试它们是否在这些途径中发挥作用。这项工作的完成将为以下领域的研究开辟新的途径：开发预测他莫昔芬治疗反应的分子筛选器，设计提高他莫昔芬对内在耐药患者的疗效的策略，以及应用新的分子方法来减缓肿瘤进展。

DESCRIPTION (provided by applicant): There is growing evidence to suggest that changes in expression of the adapter protein p130cas (Cas) in breast tumors may contribute to cancer progression and poor prognosis. In human breast tumors, Cas overexpression is correlated with a high probability of recurrence and a high incidence of intrinsic resistance to the antiestrogen tamoxifen. Antiestrogen resistance is also evident in cultured breast cancer cells that overexpress either Cas or its binding partner AND-34/BCAR3. Cas is comprised of multiple structural domains, each of which has the capacity to interact with a different array of proteins and thus promote potentially distinct functional outcomes. We hypothesize that overexpression of Cas or AND-34 activates signaling pathways through interactions with a defined subset of these proteins, ultimately leading to antiestrogen resistance and changes in cell physiology that are associated with aggressive tumor behavior and poor prognosis. This hypothesis will be tested in Aim 1 by identifying domains and downstream effectors of Cas and AND-34 that function to promote antiestrogen resistance, and investigating how these pathways coordinate with or override estrogen receptor functions during this process. In Aim 2, we will test whether Cas overexpression in cells that serve as models for early-stage breast cancer can induce changes in cell physiology and morphology that coincide with the acquisition of a more aggressive growth and invasion phenotype. Conversely, we will also test whether inhibition of Cas expression or function in cells that serve as models for late-stage breast cancer reverses some of the deleterious phenotypes exhibited by these cells. The potential functional contribution of proteins known to bind to domains that are implicated in the studies described above will be pursued in the context of each of the two Specific Aims. However, in those instances where a domain is implicated that does not have a known binding partner, or when none of the known binding proteins are found to play a role, attempts will be made in Aim 3 to identify additional binding partners and test whether they function in these pathways. Completion of this work will open new avenues of investigation into such areas as the development of molecular screens for predicting responses to tamoxifen treatment, the design of strategies for enhancing the efficacy of tamoxifen in intrinsically resistant patients, and the application of novel molecular approaches to slow tumor progression.