The Importance of EMT in Breast Cancer in African American Women

EMT 对非裔美国女性乳腺癌的重要性

• 批准号: 8035882
• 负责人: Patricia E Berg
• 金额: $ 16.87万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035882
• 关键词: African American; Age; Biological; Biological Assay; Breast Cancer Cell; Cancer cell line; Caucasians; Caucasoid Race; Cell Line; Cells; Clinical Research; Data; Diagnostic Neoplasm Staging; Disease; Drug resistance; E-Cadherin; Estrogen receptor negative; Exhibits; Frequencies; Gene Expression; Genes; Goals; Immunohistochemistry; Laboratories; Malignant Epithelial Cell; Mammary Neoplasms; Measurement; Measures; Mesenchymal; Neoplasm Metastasis; Outcome; Patients; Play; Process; RNA; Role; Sampling; Staging; Time; Tissues; Tumor Tissue; Tumor stage; Tumor-Derived; Vimentin; Woman; epithelial to mesenchymal transition; inhibitor/antagonist; malignant breast neoplasm; migration; mortality; overexpression; prevent; public health relevance; small molecule; therapeutic target; transdifferentiation; tumor; tumor progression

DESCRIPTION (provided by applicant): Our laboratory has discovered a gene, BP1, that is activated in 89% of the tumors of African American women (AAW), compared with 57% of the tumors of Caucasian women (CW). High level BP1 expression is associated with aggressive and larger tumors. Tumors of AAW are also aggressive - higher grade, larger, more frequently estrogen receptor (ER) negative, and more proliferative - resulting in an almost 50% higher mortality rate of AAW than CW with breast cancer. BP1 may also be involved in a process called the epithelial to mesenchymal transition (EMT), which is associated with transdifferentiation of malignant epithelial cells to mesenchymal cells. BP1 up-regulates the Twist gene, an inducer of EMT. EMT plays a role in breast cancer progression, invasion, metastasis, and drug resistance, making it a potential therapeutic target. Clinical studies indicate that EMT is predictive of poor outcome in many tumors. Together, these data suggest that EMT may be more frequent in tumors of AAW than CW: expression of BP1 may activate Twist, causing EMT and, independently, other genes may induce EMT, resulting in the more aggressive tumors seen in AAW. HYPOTHESES. We hypothesize that: (a) the breast tumors of AAW undergo EMT more frequently than tumors of CW, and (b) high level BP1 expression is associated with EMT. SPECIFIC AIMS. Aim 1. To determine the frequency of EMT in the tumors of AAW and CW. Aim 2. To determine the involvement of BP1 in EMT. APPROACH. Markers of EMT will be examined in 50 tumor tissues from AAW and 50 tumor tissues from CW, matched for age and stage of breast cancer. Immunohistochemistry will be used to determine the expression of EMT markers, including E-cadherin, vimentin, and Twist. Data will be correlated with clinico- pathological data available for all patients. The same markers will be measured in RNA from a subset of the tumors for which tissue is available. To discover the involvement of BP1 in EMT, the tissues and RNA samples described above will also be assessed for BP1 levels. Breast cancer cell lines derived from the tumors of AAW and CW will be studied to determine the levels of BP1 and markers of EMT. Selected cell lines expressing either low or high levels of BP1 will be used to (i) overexpress BP1 or (ii) repress BP1, respectively, followed by measurement of E-cadherin, vimentin and Twist levels. Microarrays will be used to identify additional changes in gene expression associated with BP1 and EMT. Additional assays will include measurement of invasion and migration, and observation of morphological changes after overexpression or reduction of pBP1. SIGNIFICANCE. If EMT is more prevalent in tumors of AAW than CW, genes expressed during the transition would make good targets for therapy, with the possibility of reducing or preventing metastases. If BP1 is a regulator of EMT (through Twist), there would be a strong rationale for targeting BP1 using small molecule inhibitors, siBP1 or other approaches. PUBLIC HEALTH RELEVANCE: If EMT is more prevalent in tumors of AAW than CW, genes expressed during the transition would make good targets for therapy, with the possibility of reducing or preventing metastases. If BP1 is a regulator of EMT (through Twist), there would be a strong rationale for targeting BP1 using small molecule inhibitors, siBP1 or other approaches.

描述（由申请人提供）：我们的实验室发现了一种基因BP 1，该基因在89%的非裔美国妇女（AAW）肿瘤中被激活，而白人妇女（CW）的肿瘤中为57%。高水平的BP 1表达与侵袭性和较大的肿瘤相关。AAW的肿瘤也是侵袭性的-更高级别，更大，更常见的雌激素受体（ER）阴性，更具增殖性-导致AAW的死亡率比CW乳腺癌高近50%。BP 1还可能参与称为上皮向间充质转化（EMT）的过程，其与恶性上皮细胞向间充质细胞的转分化有关。BP 1上调Twist基因，一种EMT诱导物。EMT在乳腺癌的进展、侵袭、转移和耐药性中起作用，使其成为潜在的治疗靶点。临床研究表明，EMT是许多肿瘤预后不良的预测指标。总之，这些数据表明，EMT在AAW肿瘤中可能比CW更常见：BP 1的表达可能激活Twist，导致EMT，并且独立地，其他基因可能诱导EMT，导致AAW中观察到的更具侵袭性的肿瘤。假设。我们假设：（a）AAW的乳腺肿瘤比CW的肿瘤更频繁地经历EMT，和（B）高水平的BP 1表达与EMT相关。具体目标。目标1.目的：探讨AAW和CW肿瘤中EMT的发生率。目标2.确定BP 1在EMT中的作用。APPROACH.将在来自AAW的50个肿瘤组织和来自CW的50个肿瘤组织中检查EMT标志物，其与乳腺癌的年龄和分期相匹配。免疫组织化学将用于确定EMT标志物的表达，包括E-钙粘蛋白、波形蛋白和Twist。数据将与所有患者的临床病理学数据相关。将在来自肿瘤亚组的RNA中测量相同的标志物，其中组织是可用的。为了发现BP 1参与EMT，还将评估上述组织和RNA样品的BP 1水平。将研究来自AAW和CW肿瘤的乳腺癌细胞系，以确定BP 1和EMT标志物的水平。选择的表达低或高水平BP 1的细胞系将分别用于（i）过表达BP 1或（ii）抑制BP 1，然后测量E-钙粘蛋白、波形蛋白和Twist水平。微阵列将用于鉴定与BP 1和EMT相关的基因表达的其他变化。其他试验将包括测量侵袭和迁移，以及观察pBP 1过表达或减少后的形态学变化。意义如果EMT在AAW肿瘤中比CW更普遍，则在过渡期间表达的基因将成为治疗的良好靶点，并有可能减少或预防转移。如果BP 1是EMT的调节剂（通过Twist），那么使用小分子抑制剂siBP 1或其他方法靶向BP 1将有很强的理由。 公共卫生相关性：如果EMT在AAW肿瘤中比CW更普遍，则在过渡期间表达的基因将成为治疗的良好靶点，并有可能减少或预防转移。如果BP 1是EMT的调节剂（通过Twist），那么使用小分子抑制剂siBP 1或其他方法靶向BP 1将有很强的理由。