The Role of CCN5 in Progression of Breast Cancer

CCN5 在乳腺癌进展中的作用

• 批准号: 8971986
• 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/8971986
• 关键词: Affect; Award; Awareness; Back; Basement membrane; Biological; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer cell line; Breast Carcinoma; CD29 Antigen; Cells; Clinical; Clinical Trials; Coculture Techniques; Collagen Type IV; Cyclin D1; Development; Diagnosis; Disease; Disease Progression; ERBB2 gene; Early Diagnosis; Employee Strikes; Estrogen Antagonists; Estrogen receptor negative; 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; SHH gene; Sampling; Signal Pathway; Signal Transduction; Skin Cancer; Staging; Stromal Cells; Tamoxifen; Techniques; Testing; Tetanus Helper Peptide; Therapeutic; Time; Tissue Sample; Transgenic Mice; Transgenic Organisms; Tumor Suppressor Proteins; Up-Regulation; VEGFA gene; Veterans; Woman; Work; Xenograft Model; Xenograft procedure; base; breast cancer survival; cancer cell; cell transformation; design; epithelial to mesenchymal transition; extracellular; genetic approach; hormone therapy; 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; skills; smoothened signaling pathway; tissue biomarkers; 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，是西方女性中继非黑素细胞皮肤癌之后最常见的恶性疾病。它攻击八分之一的女性（约 12%），影响到全世界几乎每个家庭，包括美国退伍军人群体。大约 30% 的确诊患者会发展为侵袭性疾病，最终无法治愈。因此，这是女性退伍军人的一个重大健康问题。尽管早期诊断的增加和新的治疗方案显着提高了 BC 的生存率，但晚期 BC 的治疗选择仍然有限。这些方案无效的原因之一是它们不针对肿瘤微环境，而肿瘤微环境在肿瘤进展中起着关键作用。因此，需要从非侵入性微环境中了解 BC 进展的病因，并利用这种认识来设计基于分子的靶向治疗。 我们最近发现，与侵入性细胞相比，基质细胞蛋白 CCN5 在非侵入性 BC 细胞系和组织样本中高表达，并且在体外发挥可塑性的负调节作用。它可以防止上皮细胞 BC 细胞中的间质转化 (EMT) 过程。此外，初步研究表明，CCN5可能通过保护生物栅栏（肌上皮层和基底膜）抑制原位导管癌（DCIS）向侵袭性BC的转变，或者可能阻止或减少侵袭性BC细胞的生长，或者两者兼而有之，并可能使ER阴性侵袭性BC细胞对激素治疗敏感。现在，我们建议使用异种移植模型、基因工程小鼠模型、基因操作的人类BC细胞系和基质细胞来建立上述前提并揭示CCN5调节癌细胞进展至侵袭的机制。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基底膜降解或两者来防止 DCIS 向浸润性导管癌转变。为了测试这一点，将在 MCFDCIS 导管内异种移植模型（MIND 模型）中使用条件敲低策略。 目标 2：我们将确定 CCN5 对 BC 肿瘤进展和生存的影响。为了测试这一点，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。 目标 3：我们将确定 CCN5 的增益是否使抗雌激素对 BC 的作用重新敏感。将使用体外和体内（异种移植物和 MNIC5 小鼠模型）。 我们将利用最先进的技术、我们开发的 Tet-op-MMTV-CCN5 小鼠模型以及我们多学科团队独特的集体专业知识来揭示 CCN5 通路在 BC 进展中的作用。 意义：拟议的研究应该对 CCN5 信号在侵袭性癌症微环境中的保护作用产生新的解释。此外，这项研究应阐明CCN5的功能作用，同时揭示新的靶点和途径，这将有助于我们的研究目标，即寻找有效的治疗试剂来对抗乳腺癌，从而改善美国退伍军人和其他绝经前和绝经后患者的预后。