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

描述(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阳性乳腺癌通常采用激素治疗，以抑制受体功能(抗雌激素)或阻止雌激素(芳香酶抑制剂)的产生。虽然这些治疗在临床上被证明是非常有效的，但对这些药物的从头耐药和获得性耐药都是一个重大问题。最令人担忧的事实是，治疗失败往往与疾病的进展和转移相关。这项提议试图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中介。它专注于三种信号分子，包括蛋白酪氨酸激酶c-Src、适配分子p130Cas(Cas)和一种名为乳腺癌抗雌激素耐药-3(BCAR3)的细胞质分子。它们中的每一个都在晚期癌症的乳腺癌细胞系中高度表达，在那些已经测量到在人类癌症中表达的病例中，侵袭性乳腺癌中也是如此。我们假设，这些蛋白通过上调增殖、存活和细胞迁移途径以及下调凋亡途径来促进对内分泌治疗和疾病进展的抵抗。本提案的目标1和目标2中概述的研究将定义由Cas、c-Src和BCAR3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控。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-BCAR3通路是否可以使ER阳性的耐药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-BCAR3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)开发治疗方法，使耐药肿瘤对这些类别的药物重新敏感；3)设计避免对单一激素治疗产生耐药性的联合疗法；以及4)开发限制乳腺癌转移扩散的新策略。公共卫生相关性：这项研究的重点是Cas-Src-BCAR3信号轴，该信号轴被假设在调节导致ER阳性细胞中侵袭性肿瘤表型和对雌激素靶向治疗的耐药性的全球反应中发挥核心作用。然而，这些效应并不局限于ER阳性细胞；无论ER状态如何，该通路高度活跃的乳腺肿瘤细胞也表现出对细胞毒治疗的抵抗力和更多的迁移/侵袭。通过更好地了解Cas、Src和BCAR3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信号；2)开发有针对性的治疗方法，以阻断特定的未受调控的通路；以及3)考虑将荷尔蒙靶向疗法与那些针对未获调控的通路的疗法(S)结合使用，以提供最大的乳腺癌治疗效果。

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.