The Role of CCN5 in Progression of Breast Cancer

CCN5 在乳腺癌进展中的作用

• 批准号: 8625184
• 负责人: Sushanta K. Banerjee
• 金额: --
• 依托单位: KANSAS CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625184
• 关键词: Affect; Award; Awareness; Back; Basement membrane; Biological; Biological Markers; Breast Cancer Cell; Breast Cancer Treatment; Breast Carcinoma; CD29 Antigen; Cancer Patient; Cancer cell line; Cells; Clinical; Clinical Trials; Coculture Techniques; Collagen Type IV; Cyclin D1; Development; Diagnosis; Disease; Disease Progression; ERBB2 gene; Early Diagnosis; Employee Strikes; Erinaceidae; Estrogen Antagonists; Estrogen Receptor Modulators; Etiology; Event; Family; Future; Genes; Genetic; Genetically Engineered Mouse; Goals; Grant; Growth; Health; Hormones; Human; In Vitro; Knock-out; Laboratories; Malignant - descriptor; Malignant Neoplasms; Mammary Tumorigenesis; Mammary gland; Measures; Mediating; Metastatic Neoplasm to the Lung; Molecular Target; Mouse Mammary Tumor Virus; Mus; Myoepithelial; Myoepithelial cell; Neoplasm Metastasis; Neuropilin-1; Noninfiltrating Intraductal Carcinoma; Outcome; Pathway interactions; Patients; Phenotype; Play; Population; Postmenopause; Preventive; Process; Proteins; Reagent; Regimen; Regulation; Research; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Skin Cancer; Staging; Stromal Cells; Tamoxifen; Techniques; Testing; Tetanus Helper Peptide; Therapeutic; Time; Tissue Sample; Tissues; Transgenic Mice; Transgenic Organisms; Tumor Suppressor Proteins; Up-Regulation; VEGFA gene; Veterans; Woman; Work; Xenograft Model; Xenograft procedure; base; cancer cell; cell transformation; design; epithelial to mesenchymal transition; extracellular; hormone therapy; human ESR1 protein; improved; in vivo; infiltrating duct carcinoma; knock-down; laminin-1; malignant breast neoplasm; migration; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; outcome forecast; overexpression; prevent; programs; public health relevance; skills; smoothened signaling pathway; tumor growth; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): Breast cancer (BC), a genetically heterogeneous disease, is the most commonly identified malignant disease in Western women after non-melanocytic skin cancer. It attacks one in eight women (~12%), impacting nearly every family worldwide, including the US Veterans population. Approximately 30% of those diagnosed will develop the invasive form of the disease, which is ultimately incurable. Therefore, it is a major health issue for women Veterans. Although increased early diagnosis and new therapeutic regimens have significantly improved BC survival, the therapeutic options for advanced stage BC are limited. One reason these regimens are not effective is that they do not target the tumor microenvironment, which plays critical roles in tumor progression. Thus, there is a need to understand the etiology of BC progression from a non- invasive microenvironment and to use this awareness for the design of a targeted, molecular based therapy. We recently discovered that the matricellular protein CCN5 is highly expressed in non-invasive BC cell lines and tissue samples, as compared to invasive ones and plays a negative regulator of plasticity in vitro. It prevents the epithelial to mesenchymal transition (EMT) process in BC cells. Furthermore, preliminary studies suggest that CCN5 may inhibit the transition of in situ ductal carcinoma (DCIS) to invasive BC through the protection of biological fences (myoepithelial layer and basement membrane), or may prevent or reduce the growth of aggressive BC cells or both and possibly make ER negative aggressive BC cells sensitive to hormone therapy. Now, we propose to establish the above premises and unravel the mechanisms of CCN5 in regulation of cancer cell progression to invasion using a xenograft model, genetically engineered mouse models, genetically manipulated human BC cell lines and stromal cells. To test this hypothesis, three specific aims are proposed: Aim 1: We will determine whether CCN5 is able to prevent DCIS to invasive ductal carcinoma transition by protecting the myoepithelial layer or basement membrane degradation or both. To test this, conditional knock- down strategies will be used in a MCFDCIS-intraductal-xenograft model (MIND model). Aim 2: We will determine the effect of CCN5 on tumor progression and survival in BC. To test this, we will use the MMTV-neu/Tet-op-MMTV-CCN5 (MNIC5) transgenic mouse model to evaluate the impact of CCN5 gains in HER-2/neu driven mammary tumorigenesis. Aim 3: We will determine whether the gain of CCN5 re-sensitizes antiestrogen's action on BC. Both in vitro and in vivo (xenografts and MNIC5 mouse model) will be used. We will use state-of-the art techniques, our development of a Tet-op-MMTV-CCN5 mouse model, and the unique collective expertise of our multi-disciplinary team to uncover the role of the CCN5 pathway in BC progression. Significance: The proposed studies should result in new explanations of the protective role of CCN5 signaling in microenvironment of invasive cancers. Moreover, this study should clarify the functional roles of CCN5, while revealing novel targets and pathways which will aid in our research goals of finding effective therapeutic reagents to battle breast cancer bringing an improved prognosis to US Veterans and other pre- and post- menopausal patients.

描述（由申请人提供）： 乳腺癌（BC）是一种遗传异质性疾病，是非斜型皮肤癌后西方女性最常见的恶性疾病。它攻击了八分之一的妇女（约12％），影响了包括美国退伍军人人口在内的全世界几乎每个家庭。大约30％的被诊断患者会发展出疾病的侵入性形式，最终是无法治愈的。因此，这是女退伍军人的主要健康问题。尽管早期诊断和新的治疗方案的增加有了明显改善的BC存活，但BC晚期的治疗选择受到限制。这些方案无效的原因之一是它们不针对肿瘤微环境，该环境在肿瘤进展中起着关键作用。因此，有必要了解从非侵入性微环境中bc进展的病因，并将这种意识用于设计目标，基于分子的治疗。 我们最近发现，与侵入性的基细胞蛋白CCN5在非侵入性BC细胞系和组织样品中高度表达，并且在体外扮演了可塑性负调节剂。它可以防止上皮 BC细胞中的间充质转变（EMT）过程。此外，初步研究表明，CCN5可能会通过保护生物围栏（肌上皮层和地下膜）来抑制原位导管癌（DCIS）对侵入性BC的过渡，或者可能预防或可以预防或减少侵袭性BC细胞的生长或可能使侵略性BC的侵略性BC细胞敏感性化。现在，我们建议建立上述前提，并使用异种移植模型，基因工程小鼠模型，基因操纵的人类BC细胞系和基质细胞来调节癌细胞进展到侵袭中CCN5的机制。为了检验这一假设，提出了三个具体目标：目标1：我们将确定CCN5是否能够通过保护肌上皮层或地下膜降解或两者兼而有之防止DCIS侵入性导管癌转变。为了测试这一点，有条件的敲低策略将用于MCFDCIS-INDADUCTAL-XENROGRAST模型（思维模型）。 AIM 2：我们将确定CCN5对BC肿瘤进展和存活的影响。为了进行测试，我们将使用MMTV-NEU/TET-OP-MMTV-CCN5（MNIC5）转基因小鼠模型来评估CCN5增益对HER-2/NEU驱动的乳腺肿瘤发生的影响。 AIM 3：我们将确定CCN5的增益是否会重新敏感抗雌激素对BC的作用。将使用体外和体内（异种移植物和MNIC5小鼠模型）。 我们将使用最先进的技术，开发TET-OP-MMTV-CCN5鼠标模型以及我们多学科团队的独特集体专业知识来揭示CCN5途径在BC进展中的作用。 意义：拟议的研究应导致对CCN5信号在侵入性癌症微环境中的保护作用的新解释。此外，这项研究应阐明CCN5的功能作用，同时揭示新的靶标和途径，这将有助于我们的研究目标，以寻找有效的治疗试剂抗乳腺癌，从而改善了美国退伍军人和其他前和绝经后患者的预后。