Regulation of Snail in breast cancer progression and metastasis

Snail在乳腺癌进展和转移中的调节作用

• 批准号: 7316187
• 负责人: Binhua P Zhou
• 金额: $ 28.69万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-13 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7316187
• 关键词: 20q13; Biology; Body part; Breast; Breast Cancer Cell; Breast Cancer Treatment; Cancer Center; Cancer cell line; Cause of Death; Cells; Cellular Morphology; Chromosomes; Clinical; Coupled; Data; Disease; Distant; Doctor of Medicine; Doctor of Philosophy; Documentation; Down-Regulation; E-Cadherin; Embryonic Development; Environment; Epithelial; Goals; Human; Incidence; Intervention; Knowledge; Life; Light; Location; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Medical Oncologist; Mesenchymal; Methods; Molecular; Mus; Neoplasm Metastasis; Neoplasms; Nodal; Nuclear; Outcome; Pathogenesis; Pathologist; Patients; Play; Prevention; Protein Overexpression; Proteins; Public Health; Publishing; Rate; Reagent; Regulation; Research; Research Personnel; Role; Scaffolding Protein; Snails; Specimen; Staging; Surgeon; Symptoms; Testing; Time; Up-Regulation; Woman; Work; base; cell motility; ductal breast carcinoma; in vivo; innovation; malignant breast neoplasm; novel; prevent; prognostic; programs; promoter; research study; success; tumor; tumor progression

DESCRIPTION (provided by applicant): Approximately 90% of breast cancer deaths are caused by metastasis, and the median survival time for patients with metastatic breast cancer is approximately 2 years. Therefore, an understanding of the mechanisms at work in the initiation and progression of metastasis is important for prevention and treatment of breast cancer. Our long-term goal is to reduce the incidence of breast cancer metastasis by gaining an understanding of the molecular mechanism underlying the initial step of breast cancer metastasis. As the master switch for epithelial-mesenchymal transition (EMT) and the initial step of metastasis, Snail plays a critical role in the initiation and progression of metastasis. Overexpression of Snail correlates with tumor grade and nodal metastasis of breast cancer, but the mechanism remains unclear. We recently demonstrated that the activity of Snail is regulated mainly by its protein stability and cellular location. Using an unbiased approach-tandem array purification (TAP) coupled with mass spectrometry analysis, we identified the interaction of Snail with EPLINb (Epithelial Protein Lost in Neoplasm). We found that downregulation of EPLINP correlated with the upregulation of Snail in breast cancer cell lines and metastatic breast cancer specimens. We further demonstrated that expression of EPLINb induces degradation of Snail and relieves suppression of the E-cadherin promoter mediated by Snail. The central hypothesis of our proposal is that EPLINb functions as a negative regulator for Snail and that loss of EPLINb in breast cancer induces the stabilization and nuclear localization of Snail, thus triggering breast cancer progression and metastasis. The objective of this proposal is to decipher the functional regulation of Snail by EPLINb in breast cancer and explore the prognostic value of EPLINb and Snail as markers of metastasis in breast cancer. Guided by strong preliminary data, we will test this hypothesis by pursuing three specific aims: (1) to delineate the regions on Snail and EPLINb required for their association; (2) to determine whether the loss of EPLINb enhances the stabilization of Snail; and (3) to define the functional regulation of Snail and EPLINb in mouse and human breast cancer. Our proposal is innovative and significant to public health because knowledge gained from this study will expand the understanding of the initiation and progression of metastasis and holds great promise for novel interventions for preventing and treating breast cancer.

描述（申请人提供）：大约90%的乳腺癌死亡是由转移引起的，转移性乳腺癌患者的中位生存时间约为2年。因此，了解转移起始和进展的机制对于预防和治疗乳腺癌非常重要。我们的长期目标是通过了解乳腺癌转移初始阶段的分子机制来降低乳腺癌转移的发生率。 Snail作为上皮间质转化（EMT）的总开关和转移的起始步骤，在转移的启动和进展中发挥着关键作用。 Snail的过度表达与乳腺癌的肿瘤分级和淋巴结转移相关，但其机制仍不清楚。我们最近证明，Snail 的活性主要受其蛋白质稳定性和细胞位置的调节。使用无偏倚的串联阵列纯化 (TAP) 方法和质谱分析，我们确定了 Snail 与 EPLINb（肿瘤中丢失的上皮蛋白）的相互作用。我们发现乳腺癌细胞系和转移性乳腺癌标本中 EPLNP 的下调与 Snail 的上调相关。我们进一步证明 EPLINb 的表达会诱导 Snail 的降解并缓解 Snail 介导的 E-钙粘蛋白启动子的抑制。我们提议的中心假设是 EPLINb 作为 Snail 的负调节因子发挥作用，乳腺癌中 EPLINb 的缺失会诱导 Snail 的稳定和核定位，从而引发乳腺癌的进展和转移。本提案的目的是破译 EPLINb 对 Snail 在乳腺癌中的功能调节，并探讨 EPLINb 和 Snail 作为乳腺癌转移标志物的预后价值。在强有力的初步数据的指导下，我们将通过追求三个具体目标来检验这一假设：(1) 描绘 Snail 和 EPLINb 关联所需的区域； (2)确定EPLINb的丢失是否增强了Snail的稳定性； (3) 明确 Snail 和 EPLINb 在小鼠和人类乳腺癌中的功能调节。我们的建议具有创新性，对公共卫生具有重要意义，因为从这项研究中获得的知识将扩大对转移的起始和进展的理解，并为预防和治疗乳腺癌的新干预措施带来巨大希望。