Mechanisms of Breast Tumor Cell Growth, Motility, and Antiestrogen Response

描述（由申请人提供）：雌激素和雌激素受体（ER）是乳腺上皮细胞增殖、分化和凋亡的关键调节因子。因此，ER阳性乳腺癌经常用旨在抑制受体功能（抗雌激素）或阻断雌激素产生（芳香酶抑制剂）的激素疗法治疗。虽然这些治疗已被证明在临床环境中非常有效，但对这些药物的新生和获得性耐药性都是一个重大问题。最令人担忧的是，治疗失败往往与疾病进展和转移有关。该提案旨在了解信号轴的调节和功能，该信号轴被假设为这些侵袭性乳腺肿瘤表型的介导者。它集中在一个三联体的信号分子，包括蛋白酪氨酸激酶c-Src，衔接分子p130 Cas（Cas），和一个细胞质分子称为乳腺癌抗雌激素抵抗-3（BCAR 3）。这些中的每一种在由晚期癌症产生的乳腺癌细胞系中高度表达，并且在已经测量了在人类癌症中表达的那些情况下，在侵袭性乳腺肿瘤中高度表达。我们假设这些蛋白质通过上调增殖、存活和细胞迁移途径以及下调凋亡途径促进对内分泌疗法的抵抗和疾病进展。本提案目标1和2中概述的研究将定义Cas、c-Src和BCAR 3激活的控制抗雌激素反应和乳腺肿瘤细胞迁移/侵袭的通路的分子组成和调节。然后，我们将把目标3转向小鼠异种移植模型，以研究抑制Cas-Src-BCAR 3通路是否可以使耐药ER阳性乳腺肿瘤对抗雌激素治疗重新敏感，并抑制ER阴性肿瘤的生长和转移。该项目的长期目标是了解Cas-Src-BCAR 3信号网络的调节、功能和分子组成，以便能够1）更好地预测哪些肿瘤将具有较高的耐药性; 2）开发使耐药肿瘤对这些类别药物重新敏感的治疗方法; 3）设计规避对单药治疗的抗性的组合疗法;和4）开发用于限制乳腺肿瘤的转移性扩散的新策略。公共卫生相关性：本研究关注Cas-Src-BCAR 3信号传导轴，假设其在调节导致ER阳性细胞中侵袭性肿瘤表型和对雌激素靶向疗法的抗性的整体应答中发挥核心作用。然而，这些作用并不局限于ER阳性细胞;该途径高度活跃的乳腺肿瘤细胞也表现出对细胞毒性疗法的抗性和迁移/侵袭增加，而与ER状态无关。通过更好地理解Cas、Src和BCAR 3信号网络的组成、功能和调节，有可能1）更好地定义预测哪些肿瘤将无法进行内分泌治疗的分子特征; 2）开发靶向治疗，以阻断被解除管制的特定途径，以及3）考虑将乳腺靶向治疗与靶向解除调节的途径的治疗组合使用，以提供对乳腺癌的最大治疗功效。

DESCRIPTION (provided by applicant): Estrogen and the estrogen receptors (ERs) are critical regulators of breast epithelial cell proliferation, differentiation, and apoptosis. Consequently, ER-positive breast cancers are frequently treated with hormonal therapies designed to inhibit receptor function (antiestrogens) or block production of estrogens (aromatase inhibitors). While these treatments have proven to be extremely effective in the clinical setting, both de novo and acquired resistance to these drugs are a significant problem. Most concerning is the fact that treatment failure often correlates with disease progression and metastasis. This proposal seeks to understand the regulation and function of a signaling axis that is hypothesized to function as a mediator of these aggressive breast tumor phenotypes. It focuses on a triad of signaling molecules that includes the protein tyrosine kinase c-Src, the adapter molecule p130Cas (Cas), and a cytoplasmic molecule called breast cancer antiestrogen resistance-3 (BCAR3). Each of these is highly expressed in breast cancer cell lines arising from advanced cancers and, in those cases where expression in human cancers has been measured, aggressive breast tumors. We hypothesize that these proteins promote resistance to endocrine therapies and disease progression through up-regulation of proliferative, survival, and cell migration pathways and down-regulation of apoptotic pathways. The studies outlined in Aims 1 and 2 of this proposal will define the molecular composition and regulation of pathways activated by Cas, c-Src, and BCAR3 that control antiestrogen responses and cell migration/invasion of breast tumor cells. We will then turn in Aim 3 to mouse xenograft models to investigate whether inhibition of the Cas-Src-BCAR3 pathway can re-sensitize resistant ER-positive breast tumors to antiestrogen therapies and inhibit the growth and metastasis of ER-negative tumors. The long-term goal of this project is to gain an understanding of the regulation, function, and molecular composition of Cas-Src-BCAR3 signaling networks in order to be able to 1) better predict which tumors will have a high likelihood of exhibiting resistance; 2) develop therapeutic approaches for re-sensitizing resistant tumors to these classes of drugs; 3) design combinatorial therapies that circumvent the resistance to single-agent hormona treatment; and 4) develop novel strategies for limiting metastatic spread of breast tumors. PUBLIC HEALTH RELEVANCE: This study focuses on the Cas-Src-BCAR3 signaling axis, which is hypothesized to play a central role in regulating global responses that contribute to aggressive tumor phenotypes and resistance to estrogen- targeted therapies in ER-positive cells. However, these effects are not restricted to ER-positive cells; breast tumor cells in which this pathway is highly active also exhibit resistance to cytotoxic therapies and increased migration/invasion, irrespective of ER status. By better understanding the composition, function, and regulation of Cas, Src, and BCAR3 signaling networks, it may be possible to 1) better define molecular signatures that will predict which tumors will fail endocrine therapies; 2) develop targeted treatments to block the specific pathways that are deregulated, and 3) consider the use of hormonally- targeted therapies in combination with those targeting the deregulated pathway(s) to provide maximum efficacy of treatment for breast cancer.