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: 8585768
• 负责人: Susan A Miranda
• 金额: $ 20.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8585768
• 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女性中第二常见的癌症类型。人们对乳腺癌中受致癌突变影响的基因了解很多。然而，人们对转移至关重要的分子事件知之甚少，而转移是癌症死亡的主要原因。三阴性 (TN)（即缺乏 ER 和 HER2 表达[或过度表达]以及孕激素受体 [PR]）乳腺癌亚型具有高度转移性。我们的团队已证明 Wnt10b/b-连环蛋白/HMGA2 信号在三阴性乳腺癌 (TNBC) 和基底样癌症中过度激活。我们在翻译模型中发现，Wnt10b/¿-连环蛋白信号传导会触发肿瘤起始细胞中的高 HMGA2 活性和细胞周期增殖，从而导致人和小鼠的三阴性乳腺肿瘤。重要的是，我们的小组已经表明，WNT10B 和 HMGA2 都与预测生存结果具有显着相关性，并且 HMGA2 单独可以预测 TNBC 的转移。 TNBC 有转移倾向，主要转移至脑（30%）和肺（40%）。相比之下，其他乳腺癌亚型转移至肝脏（30%）和骨骼（40%）。与乳腺癌的其他亚型（ER¿ 和 HER2 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重大挑战，因为其潜在的分子机制仍不清楚，特别是它如何优先转移到肺部。 MMTV-Wnt10b-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，Wnt10bLacZ 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 Wnt10bLacZ 肺转移肿瘤细胞表达上皮间质转化 (EMT) 标记物，其特征是高表达 HMGA2 和对转移定植至关重要的因子。利用特异性 Wnt/¿-连环蛋白抑制剂 ICG-001 和 HMGA2 沉默可阻断增殖和 N-CADHERIN 表达，同时恢复 E-CADHERIN 和 WNT7A 水平。初步数据表明，HMGA2 的沉默可以阻断体内肺转移，并可以调节 b-catenin/CBP HAT-Activity 靶向的基因子集上 H3K4me3 的状态。我们将研究 HMGA2 介导的表观遗传活性调节 EMT 和肺转移的重要机制。我们的第一个目标是使用转移性小鼠 Wnt10bLacZTG 细胞和 HMGA2 沉默的人三阴性乳腺癌细胞系来研究 HMGA2 在肺转移中的体内作用。我们的第二个目标是通过使用 HMGA2、H3K4me3、H3K27me3 和 H3K9Ac 抗体进行 ChIP 分析，评估 ¿-连环蛋白-CBP/HAT 介导的组蛋白修饰对 EMT 特征、分化、增殖和肿瘤抑制基因启动子的变化，从而确定 HMGA2 在肺转移中的功能作用。我们的研究结果可能会改变转移性 TNBC 肿瘤的治疗方法。