The role of WNT10B and HMGA2 in Lung Metastasis in Triple Negative Breast Cancer

WNT10B和HMGA2在三阴性乳腺癌肺转移中的作用

• 批准号: 8702123
• 负责人: Susan A Miranda
• 金额: $ 15.82万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-16 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702123
• 关键词: Activity Cycles; Adult; Affect; African American; Age; Aggressive behavior; Antibodies; Body mass index; Brain; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Feeding; Cancer Etiology; Cancer Patient; Cancer cell line; Caucasians; Caucasoid Race; Cell Cycle; Cells; Cessation of life; Chromatin Structure; Clinic; Data; Development; Diagnosis; E-Cadherin; ERBB2 gene; Embryo; Embryonic Development; Epigenetic Process; Epithelial; Ethnic group; Europe; Event; Galactosidase; Gene Targeting; Genes; Goals; Grant; HMGA2 Protein; HMGA2 gene; Human; In Vitro; Internal Ribosome Entry Site; LacZ Genes; Link; Liver; Lung; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Menarche; Mesenchymal; Mesenchymal Stem Cells; Metastatic Neoplasm to the Lung; Modeling; Molecular; Molecular Medicine; Mouse Mammary Tumor Virus; Mus; Mutation; Neoadjuvant Therapy; Neoplasm Metastasis; North Carolina; Oncogenic; Outcome; Pathway interactions; Personal Communication; Play; Premenopause; Progesterone Receptors; Property; Regimen; Resistance; Risk Factors; Role; Signal Transduction; Staging; Stem cells; Surveys; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Tumor Suppressor Genes; United States; WNT7A gene; Woman; base; bone; breast cancer diagnosis; breast tumorigenesis; cancer type; chemotherapy; combat; epithelial to mesenchymal transition; histone modification; in vivo; inhibitor/antagonist; insight; killings; malignant breast neoplasm; mortality; mouse model; novel; overexpression; prevent; programs; promoter; public health relevance; research study; restoration; stem; therapeutic target; triple-negative invasive breast carcinoma; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Breast cancer represents the second most commonly diagnosed cancer type amongst women in the United States and Europe. Much is known about the genes that are affected by cancer-causing mutations in breast cancer; however, less is known about molecular events that are crucial for metastasis, which is the major cause of cancer mortality. The triple negative (TN) (i.e. lacking expression [or overexpression] of ER and HER2, as well as progesterone receptor [PR]) breast cancer subtype is highly metastatic. Wnt10b/b- catenin/HMGA2 signaling has been shown by our group to over-activated in triple-negative breast cancers (TNBC) and basal-like cancers. We uncovered in a translational model that Wnt10b/¿-catenin signaling triggers high HMGA2 activity and cell cycle proliferation in tumor-initiating cells leading to triple-negative mammary tumors in human and mice. Importantly our group has shown that both WNT10B and HMGA2 have significant correlation with predicting survival outcome and HMGA2 alone could predict metastasis for TNBC. TNBC has a propensity to metastasize, mainly to the brain (30%) and lung (40%). In contrast, other breast cancer subtypes metastasize to liver (30%) and bone (40%). Unlike other subtypes of breast cancer (ER¿ and HER2 positive tumors) there is no targeted therapy for TNBC. A therapeutic regimen for TNBC remains a major challenge in the clinics because the underlying molecular mechanisms are still not well understood-in particular how it preferentially metastasizes to the lung. MMTV-Wnt10b-IRES-LacZ transgenic mouse mammary gland tumors give rise to rare spontaneous primary lung metastasis (<0.30%). However, Wnt10bLacZ-driven tumor-initiating cells robustly induce pulmonary metastasis (>60%) in syngeneic mice. Isolated Wnt10bLacZ lung metastasis tumors cells with mesenchymal stem-cell properties express epithelial-to- mesenchymal transition (EMT) markers featuring high expression of HMGA2 and factors critical for metastatic colonization. Utilizing both a specific Wnt/¿-catenin inhibitor ICG-001 and silencing of HMGA2 blocks proliferation and N-CADHERIN expression with concurrent restoration of E-CADHERIN and WNT7A levels. Preliminary data illustrate that silencing of HMGA2 can block lung metastasis in vivo and can regulate the status of H3K4me3 on a subset of genes that are targeted by b-catenin/CBP HAT-Activity. We will study the underlining mechanism(s) by which HMGA2-mediated epigenetic activity regulates EMT and lung metastasis. Our first aim is to study the in vivo role of HMGA2 in lung metastasis using both metastatic mouse Wnt10bLacZTG cells and human triple negative breast cancer cell lines that have been silenced for HMGA2. Our second aim is to determine the functional role of HMGA2 in lung metastasis by assessing changes in ¿-catenin-CBP/HAT-mediated histone modifications on promoters of EMT-signature, differentiation, proliferation and tumor suppressor genes by ChIP analysis using antibodies to HMGA2, H3K4me3, H3K27me3, and H3K9Ac. Our findings may alter therapeutics for the metastatic TNBC tumors.

描述（由申请人提供）：乳腺癌是美国和欧洲妇女中第二大最常见的癌症类型。人们对乳腺癌中受致癌突变影响的基因了解很多;然而，对转移至关重要的分子事件知之甚少，转移是癌症死亡的主要原因。三阴性（TN）（即缺乏ER和HER 2以及孕酮受体[PR]的表达[或过表达]）乳腺癌亚型是高度转移性的。Wnt 10 B/B-连环蛋白/HMGA 2信号转导在三阴性乳腺癌（TNBC）和基底样癌中被过度激活。我们在一个翻译模型中发现，Wnt 10 b/<$-catenin信号在肿瘤起始细胞中触发高HMGA 2活性和细胞周期增殖，导致人类和小鼠的三阴性乳腺肿瘤。重要的是，我们的研究小组已经表明，WNT 10 B和HMGA 2两者与预测生存结果具有显著相关性，并且单独的HMGA 2可以预测TNBC的转移。 TNBC有转移的倾向，主要转移到大脑（30%）和肺（40%）。相比之下，其他乳腺癌亚型转移到肝脏（30%）和骨骼（40%）。与其他乳腺癌亚型（ER和HER 2阳性肿瘤）不同，TNBC没有靶向治疗。TNBC的治疗方案仍然是临床上的一个主要挑战，因为其潜在的分子机制仍然没有得到很好的理解，特别是它如何优先转移到肺部。MMTV-Wnt 10 b-IRES-LacZ转基因小鼠乳腺肿瘤引起罕见的自发性原发性肺转移（<0.30%）。然而，Wnt 10 bLacZ驱动的肿瘤起始细胞在同基因小鼠中强烈诱导肺转移（>60%）。具有间充质干细胞特性的分离的Wnt 10 bLacZ肺转移肿瘤细胞表达上皮-间充质转化（EMT）标志物，其特征在于高表达HMGA 2和转移定植的关键因子。利用特异性Wnt/β-连环蛋白抑制剂ICG-001和沉默HMGA 2阻断增殖和N-CADHERIN表达，同时恢复E-CADHERIN和WNT 7A水平。初步数据表明，HMGA 2的沉默可以阻断体内肺转移，并可以调节由b-连环蛋白/CBP HAT活性靶向的基因子集上的H3 K4 me 3的状态。我们将研究HMGA 2介导的表观遗传活性调节EMT和肺转移的潜在机制。我们的第一个目的是使用转移性小鼠Wnt 10 bLacZTG细胞和HMGA 2沉默的人三阴性乳腺癌细胞系来研究HMGA 2在肺转移中的体内作用。我们的第二个目的是通过使用HMGA 2、H3 K4 me 3、H3 K27 me 3和H3 K9 Ac的抗体进行ChIP分析，评估EMT特征、分化、增殖和肿瘤抑制基因的启动子上的<$-连环蛋白-CBP/HAT介导的组蛋白修饰的变化，确定HMGA 2在肺转移中的功能作用。我们的发现可能会改变转移性TNBC肿瘤的治疗方法。