Structure and Function of BCAR1 and BCAR3 Association in Breast Cancer Malignancy

BCAR1 和 BCAR3 关联在乳腺癌恶性肿瘤中的结构和功能

基本信息

批准号：
9042810
负责人：
ELENA B PASQUALE
金额：
$ 2.06万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9042810
关键词：
Adriamycin PFS Affect Anoikis Antibodies Antineoplastic Agents Apoptotic BCAR1 gene BCAR3 gene Binding Binding Proteins Biochemical Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment C-terminal Cancer Cell Growth Cancer Etiology Caspase Cell Proliferation Cells Cessation of life Characteristics Complex Development Drug resistance ERBB2 gene Engineering Environment Eph Family Receptors Estrogen Antagonists Estrogen receptor positive Exhibits Family Focal Adhesions Future Genes Goals Growth Guanine Nucleotide Exchange Factors Guanine Nucleotides Guanosine Triphosphate Phosphohydrolases Integrins Investigation Joints Knowledge Lead Light Malignant - descriptor Malignant Neoplasms Mediating Mediator of activation protein Modification Molecular Molecular Conformation Mus Names Neoplasm Metastasis Oncogenic Pathogenesis Pharmaceutical Preparations Play Proline Protein Family Proteins Receptor Protein-Tyrosine Kinases Relative (related person)Research Personnel Resistance Resistance development Resolution Role Scaffolding Protein Serine Signal Pathway Signal Transduction Structure Substrate Domain Woman Work Xenograft Model adhesion receptor base biological systems cancer cell chemotherapeutic agent chemotherapy coping ena protein human BCAR1 protein human RIPK1 protein insight interdisciplinary approach kinase inhibitor malignant breast neoplasm member migration mortality mouse model novel novel therapeutics overexpression receptor binding src Homology Region 2 Domain targeted treatment therapy design tool tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer deaths in women, despite a number of treatment options. Most breast cancers are estrogen receptor-positive and commonly treated with anti-estrogens, while antibodies and kinase inhibitors are used to treat cancers that overexpress the HER2 receptor tyrosine kinase. Unfortunately, tumors are often intrinsically resistant or develop resistance to these drugs due to overexpression of specific genes. One of these genes is the scaffolding protein BCAR1 (breast cancer anti- estrogen resistance 1 or p130Cas), which is a well-known key component of the signaling pathways that regulate cell proliferation, survival and migration/invasion downstream of integrin adhesion receptors. BCAR1 is also a critical node in HER2 oncogenic signaling pathways and mediator of resistance to adriamycin, a drug frequently used to treat breast cancers that do not respond to anti-estrogens or HER2-targeted therapies. Thus, BCAR1 is a central player in the signaling networks that control breast cancer malignancy. Another important but poorly characterized factor in anti-estrogen resistance is the SH2 domain-containing protein BCAR3, a member of a family of three proteins that also includes SHEP1, which we identified in a screen for Eph receptor tyrosine kinase-binding molecules. Members of the BCAR1 and BCAR3 families function in a concerted manner through direct association of their C-terminal regions, but the structure of their complexes has eluded investigators. To gain insight into these crucial yet enigmatic assemblies, we have solved the first crystal structure of a BCAR1-BCAR3 family complex, that of BCAR1 and SHEP1, revealing a novel type of protein interaction. The SHEP1 C-terminal region overall resembles a Cdc25-type guanine nucleotide exchange factor domain. However, crucial regions are altered by BCAR1 binding, resulting in a "closed" conformation of SHEP1 that cannot bind Ras GTPases. We now seek to unravel the mechanistic basis of breast cancer malignancy and resistance to chemotherapy mediated by BCAR1 association with BCAR3, a protein related to SHEP1 but with distinct differences in key features. Thus, we propose a multidisciplinary approach that integrates a spectrum of effective tools ranging from high resolution structural and biochemical analysis to functional studies in engineered cancer cells in culture and mouse breast cancer xenograft models. Our goals will be accomplished by (1) unraveling the molecular details of the BCAR1-BCAR3 signaling association to precisely define the regulatory modifications occurring upon complex formation; and (2) elucidating the role of the BCAR-BCAR3 association in breast cancer growth, invasiveness and resistance to chemotherapy. Our studies will lead to a new understanding of the BCAR1-BCAR3 signaling node as well as complexes of related proteins, and shed light on how breast cancer cells acquire the malignant characteristics that enable them to metastasize and cope with chemotherapeutic insults. Thus, this work will ultimately provide a new basis for developing treatment options to overcome cancer drug resistance.

描述（由申请人提供）：尽管有多种治疗选择，但乳腺癌仍是女性癌症死亡的第二大原因。大多数乳腺癌呈雌激素受体阳性，通常采用抗雌激素治疗，而抗体和激酶抑制剂则用于治疗过度表达 HER2 受体酪氨酸激酶的癌症。不幸的是，由于特定基因的过度表达，肿瘤通常对这些药物具有内在耐药性或产生耐药性。其中一个基因是支架蛋白 BCAR1（乳腺癌抗雌激素抵抗 1 或 p130Cas），它是调节整合素粘附受体下游细胞增殖、存活和迁移/侵袭的信号通路的众所周知的关键组成部分。 BCAR1 也是 HER2 致癌信号通路中的关键节点，也是阿霉素耐药性的介质，阿霉素是一种常用于治疗对抗雌激素或 HER2 靶向疗法无反应的乳腺癌的药物。因此，BCAR1 是控制乳腺癌恶性肿瘤的信号网络中的核心角色。抗雌激素抵抗中另一个重要但特征不明确的因素是含有 SH2 结构域的蛋白质 BCAR3，它是三个蛋白质家族的成员，该家族还包括 SHEP1，我们在 Eph 受体酪氨酸激酶结合分子的筛选中发现了 SHEP1。 BCAR1 和 BCAR3 家族的成员通过其 C 末端区域的直接关联以协调一致的方式发挥作用，但其复合物的结构一直困扰着研究人员。为了深入了解这些关键但神秘的组装体，我们解析了 BCAR1-BCAR3 家族复合物的第一个晶体结构，即 BCAR1 和 SHEP1 的晶体结构，揭示了一种新型的蛋白质相互作用。 SHEP1 C 末端区域总体上类似于 Cdc25 型鸟嘌呤核苷酸交换因子结构域。然而，BCAR1 结合改变了关键区域，导致 SHEP1 形成“封闭”构象，无法结合 Ras GTPases。我们现在试图揭示 BCAR1 与 BCAR3 相关性介导的乳腺癌恶性肿瘤和化疗耐药的机制基础，BCAR3 是一种与 SHEP1 相关的蛋白质，但在关键特征上有明显差异。因此，我们提出了一种多学科方法，整合了一系列有效的工具，从高分辨率结构和生化分析到培养工程癌细胞和小鼠乳腺癌异种移植模型的功能研究。我们的目标将通过以下方式实现：(1) 揭示 BCAR1-BCAR3 信号关联的分子细节，以精确定义复合物形成时发生的调控修饰； (2) 阐明 BCAR-BCAR3 关联在乳腺癌生长、侵袭性和化疗耐药性中的作用。我们的研究将带来对 BCAR1-BCAR3 信号节点以及相关蛋白复合物的新认识，并揭示乳腺癌细胞如何获得恶性特征，从而使它们能够转移和应对化疗损伤。因此，这项工作最终将为开发克服癌症耐药性的治疗方案提供新的基础。