Analysis of AND-34 in human breast cancer

AND-34 在人类乳腺癌中的分析

• 批准号: 7463690
• 负责人: ADAM LERNER
• 金额: $ 22.97万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463690
• 关键词: 4-Hydroxy-Tamoxifen; Affect; Antiestrogen Therapy; BCAR1 gene; BCAR3 gene; Binding; Breast Cancer Cell; Breast Carcinoma; Cancer cell line; Cells; Clinical; Complex; Cyclins; Disease; Dominant-Negative Mutation; EGF gene; Enhancers; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptors; Estrogens; Event; Family member; Faslodex(ICI 182,780); Focal Adhesions; Gene Family; Genes; Genetic; Growth Factor; Growth Factor Receptors; Heregulin; Homologous Gene; Human; ICI 182780; Immunofluorescence Immunologic; Immunohistochemistry; Immunoprecipitation; Insertional Mutagenesis; Insulin-Like Growth Factor I; Ligands; Mammary Gland Parenchyma; Mammary Neoplasms; Mediating; Mus; Numbers; Outcome; Peptides; Phosphorylation; Phosphotransferases; Play; Principal Investigator; Process; Protein Overexpression; Proteins; Receptor Protein-Tyrosine Kinases; Resistance; Retroviridae; Role; SH2D3A gene; Signal Transduction; Specimen; Tamoxifen; Tissues; Transactivation; Up-Regulation; Work; adapter protein; hormone therapy; human BCAR1 protein; malignant breast neoplasm; novel; programs; promoter; src Homology Region 2 Domain; src-Family Kinases

DESCRIPTION (provided by applicant): The mechanisms by which human breast carcinomas acquire resistance to antiestrogen therapy remain incompletely understood. In an unbiased search for genes which regulate this process, Dorssers et al determined that upregulation of either a novel protein, BCAR3, or the focal adhesion adapter protein p130Cas are reproducible genetic events that induce such antiestrogen resistance. In concurrent and independent work, we cloned murine AND-34/BCAR3 and demonstrated that it associates with p130Cas through a Cdc25 GEF-like domain. Using Western analysis, we find that AND-34 is expressed at high levels in a subset of human breast carcinomas but not normal breast tissue. We subsequently determined that overexpression of AND-34 induces PI3K, Akt and Rac activation in breast cancer cell lines. Specific Aims: 1) To determine the mechanism by which overexpression of AND-34 in human breast cancer cells induces PI3K activation, we will: A) Examine whether AND-34 associates with and positively regulates PI3K activation by transmembrane tyrosine kinase receptors in breast cancer cell lines. This work will include an analysis of signaling in AND-34 -/- tissues; B) Examine the role of p130Cas in AND-34-mediated PI3K activation; C) Examine the role of Src kinases in such PI3K activation. 2) To determine how AND-34 and related gene family members affect PI3K signaling and clinical outcome in primary human breast cancers and to examine the effect of AND-34 on ER signaling, we will: A) Contrast the ability of human NSP1, AND-34 and NSP-3 to induce Akt and Rac activation and antiestrogen resistance in human breast cancer cell lines. B) Determine by Western analysis whether NSP1, AND-34 or NSP-3 expression in primary human breast cancer specimens correlates with PI3K activation or ERa expression; C) Determine by immunohistochemistry whether NSP1, AND-34 or NSP-3 expression in primary human breast cancer specimens correlates with ERa expression, disease-free or overall survival. D) Determine if AND-34 overexpression induces ligand-independent ERa-mediated ERE transactivation.

描述（由申请人提供）：人类乳腺癌对抗雌激素治疗产生耐药性的机制仍不完全清楚。在对调节这一过程的基因的无偏搜索中，Dorssers等人确定，一种新蛋白BCAR 3或粘着斑衔接蛋白p130 Cas的上调是诱导这种抗雌激素抗性的可重复的遗传事件。在同时和独立的工作中，我们克隆了小鼠AND-34/BCAR 3，并证明它通过Cdc 25 GEF样结构域与p130 Cas相关。使用Western分析，我们发现AND-34以高水平表达 在人类乳腺癌的一个子集中，而不是在正常乳腺组织中。我们随后确定，在乳腺癌细胞系中，AND-34的过表达诱导PI 3 K、Akt和Rac活化。具体目标：1）为了确定人乳腺癌细胞中AND-34的过表达诱导PI 3 K活化的机制，我们将：A）检查AND-34是否与乳腺癌细胞系中跨膜酪氨酸激酶受体的PI 3 K活化相关并正向调节PI 3 K活化。这项工作将包括分析AND-34 -/-组织中的信号传导; B）检查p130 Cas在AND-34介导的PI 3 K活化中的作用; C）检查Src激酶在这种PI 3 K活化中的作用。2)为了确定AND-34和相关的 基因家族成员影响PI 3 K信号传导和原发性人类乳腺癌的临床结果 A）比较人NSP 1、AND-34和NSP-3诱导人Akt和Rac活化和抗雌激素抗性的能力， 乳腺癌细胞系。B）通过Western分析确定原发性人乳腺癌标本中NSP 1、AND-34或NSP-3表达是否与PI 3 K活化或ER α表达相关; 在原发性人乳腺癌标本中，与ER α表达、无病生存期或总生存期相关。D）确定AND-34过表达是否诱导配体非依赖性ER α介导的ERE反式激活。

项目成果

Loss of AND-34/BCAR3 expression in mice results in rupture of the adult lens.

小鼠 AND-34/BCAR3 表达缺失会导致成年晶状体破裂。

• 发表时间: 2009
• 期刊: Molecular vision
• 影响因子: 2.2
• 作者: Near,RichardI;Smith,RichardS;Toselli,PaulA;Freddo,ThomasF;Bloom,AlexanderB;VandenBorre,Pierre;Seldin,DavidC;Lerner,Adam
• 通讯作者: Lerner,Adam