HMGA1 in Tumor Progression in Breast Cancer

HMGA1 在乳腺癌肿瘤进展中的作用

• 批准号: 8061682
• 负责人: Linda M S Resar
• 金额: $ 17.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061682
• 关键词: Address; Adult; Affect; American; Automobile Driving; Binding Proteins; Biological Markers; Breast; Breast Cancer Cell; Breast Cancer Detection; CD44 gene; Cancer Biology; Cancer Etiology; Cancer Model; Cancer cell line; Cell Culture Techniques; Cell Death; Cell Line; Cells; Cessation of life; Chromatin; Clinical; Clinical Data; Cultured Cells; Data; Detection; Development; Diagnosis; Disease; ERBB2 gene; Embryonic Development; Ensure; Gene Expression; Gene Targeting; Genes; Genetic Programming; Goals; Grant; HMGA1 gene; HMGA1b Protein; Human; Image; Immunodeficient Mouse; Injection of therapeutic agent; Knowledge; Koreans; Lead; Lung; MCF7 cell; Malignant Neoplasms; Mammary Neoplasms; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Profiling; Mus; Neoplasm Metastasis; Normal tissue morphology; Oncogenes; Oncogenic; Oncologist; Outcome; P-Cadherin; Pathologist; Pathway interactions; Patients; Phenotype; Play; Population; Positioning Attribute; Primary Neoplasm; Process; Proteins; Reagent; Research Personnel; Resistance; Resources; Role; Sampling; Specimen; Staging; Staphylococcal Protein A; Stem cells; Tail; Tissue Microarray; Tissues; Transgenic Mice; Tumor Tissue; Tumorigenicity; Undifferentiated; Veins; Veterinarians; Woman; Work; Xenograft procedure; anticancer research; base; cancer cell; cancer stem cell; cellular transduction; coping; design; embryonic stem cell; epithelial to mesenchymal transition; experience; gain of function; human disease; immunoreactivity; in vivo; innovation; knock-down; loss of function; malignant breast neoplasm; migration; mortality; multidisciplinary; neoplastic cell; new therapeutic target; novel; outcome forecast; overexpression; prevent; public health relevance; stem; stemness; success; therapeutic target; therapy resistant; tool; transcription factor; tumor; tumor progression

DESCRIPTION (provided by applicant): Despite progress in the detection and treatment of metastatic breast cancer, mortality from this disease remains high because current therapies are limited by the emergence of cancer cells that are resistant to treatment and capable of metastatic progression. Increasing evidence suggests that these cells develop, in part, because they behave like stem cells and thereby evade cell death induced by therapies which target rapidly dividing tumor cells. This proposal is directed at elucidating molecular pathways important in metastatic progression and "stemness" in breast cancer with the goal of identifying novel therapeutic targets and biomarkers. Our focus is the HMGA1 oncogene because recent findings suggest that it plays a critical role in both of these processes. This gene encodes the HMGA1a and HMGA1b chromatin binding proteins, which function in modulating gene expression. HMGA1 is highly expressed during embryogenesis, but not in adult tissues. Strikingly, HMGA1 is also overexpressed in virtually all high-grade (poorly differentiated) human cancers studied to date. We first established that HMGA1 induces oncogenic transformation in cultured cells derived from normal breast cells. HMGA1 also causes aggressive cancers in transgenic mice and promotes an epithelial-to-mesenchymal transition (EMT) in MCF-7 breast cells. Conversely, inhibiting its expression blocks transformation phenotypes in high-grade, human breast cancer cell lines and prevents metastatic progression in some tumor models. A recent study also found that HMGA1 is among a list of 9 core transcription factors enriched in high-grade/poorly differentiated breast cancers and normal embryonic stem cells, further implicating HMGA1 as a key regulator in breast cancer progression and stem cells. Taken together, these findings suggest that HMGA1 orchestrates transcriptional networks that maintain a primitive, poorly differentiated state, both in breast cancer and stem cells. Based on these findings, we hypothesize that HMGA1 drives tumor progression by inducing transcriptional networks that maintain an undifferentiated, "stem-like" phenotype. Here, we propose studies to determine if HMGA1 is a biomarker and potential therapeutic target in metastatic breast cancer. We will also begin studies to determine how HMGA1 drives tumor progression in breast cancer. Using our unique resources, we propose the following Specific Aims: 1.) Determine if HMGA1 can serve as a biomarker for more advanced, less differentiated breast cancer using a tissue microarray with primary breast tumors and detailed clinical data from >500 patients, 2.) Elucidate the role of HMGA1 in tumor progression and the stem-cell phenotype using gain-of- function/loss-of-function approaches, and, 3.) Identify the molecular signature of HMGA1 in metastatic breast cancer and begin to define the functional significance of downstream transcriptional targets. Results from our studies will elucidate novel molecular circuitry important in tumor progression and should lead to the discovery of cellular pathways that could be targeted in therapy for metastatic breast cancer. PUBLIC HEALTH RELEVANCE: Although metastatic breast cancer is a common and highly lethal cancer that affects women worldwide, the cellular pathways that mediate tumor progression and resistance to therapy are poorly understood. To address this knowledge gap, we propose to study the HMGA1 oncogene, which is highly expressed in advanced breast cancer and embryonic stem cells. Results from our studies should enhance our understanding of how breast cancer progresses and provide the basis to design better therapies directed at these resistant cells.

描述（由申请人提供）：尽管在转移性乳腺癌的检测和治疗方面取得了进展，但这种疾病的死亡率仍然很高，因为目前的治疗受到对治疗具有抗性并能够转移进展的癌细胞的出现的限制。越来越多的证据表明，这些细胞的发展，部分是因为它们的行为像干细胞，从而逃避由靶向快速分裂的肿瘤细胞的治疗诱导的细胞死亡。该提案旨在阐明乳腺癌转移进展和“干性”的重要分子途径，目的是确定新的治疗靶点和生物标志物。我们的重点是HMGA 1癌基因，因为最近的研究结果表明，它在这两个过程中发挥了关键作用。该基因编码HMGA 1a和HMGA 1b染色质结合蛋白，其在调节基因表达中起作用。HMGA 1在胚胎发生期间高度表达，但在成人组织中不表达。引人注目的是，HMGA 1在迄今为止研究的几乎所有高级别（低分化）人类癌症中也过表达。我们首先确定HMGA 1诱导来自正常乳腺细胞的培养细胞中的致癌转化。HMGA 1还导致转基因小鼠的侵袭性癌症，并促进MCF-7乳腺细胞的上皮向间质转化（EMT）。相反，抑制其表达可阻断高级别人乳腺癌细胞系中的转化表型，并防止某些肿瘤模型中的转移进展。最近的一项研究还发现，HMGA 1是在高级别/低分化乳腺癌和正常胚胎干细胞中富集的9种核心转录因子之一，进一步暗示HMGA 1是乳腺癌进展和干细胞的关键调节因子。总之，这些研究结果表明，HMGA 1协调转录网络，保持一个原始的，分化不良的状态，无论是在乳腺癌和干细胞。基于这些发现，我们假设HMGA 1通过诱导维持未分化的“干细胞样”表型的转录网络来驱动肿瘤进展。在这里，我们提出了研究，以确定HMGA 1是否是转移性乳腺癌的生物标志物和潜在的治疗靶点。我们还将开始研究，以确定HMGA 1如何驱动乳腺癌的肿瘤进展。利用我们独特的资源，我们提出以下具体目标：1。使用原发性乳腺肿瘤的组织微阵列和来自>500名患者的详细临床数据，确定HMGA 1是否可以作为更晚期、低分化乳腺癌的生物标志物。使用功能获得/功能丧失方法阐明HMGA 1在肿瘤进展和干细胞表型中的作用，以及，3.）确定转移性乳腺癌中HMGA 1的分子特征，并开始确定下游转录靶点的功能意义。我们的研究结果将阐明肿瘤进展中重要的新分子回路，并将导致发现可用于转移性乳腺癌治疗的细胞通路。 公共卫生关系：虽然转移性乳腺癌是一种常见的高致死性癌症，影响世界各地的妇女，介导肿瘤进展和耐药性的细胞途径知之甚少。为了解决这一知识缺口，我们建议研究HMGA 1癌基因，该基因在晚期乳腺癌和胚胎干细胞中高度表达。我们的研究结果应该增强我们对乳腺癌进展的理解，并为设计针对这些耐药细胞的更好疗法提供基础。