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Role of CCN6 (WISP3) in the progression and metastasis of breast cancer

CCN6 (WISP3) 在乳腺癌进展和转移中的作用

基本信息

批准号：
10676901
负责人：
Celina G Kleer
金额：
$ 37.05万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676901
关键词：
Address African African American African American population American Area Behavior Binding Biological Breast Breast Cancer Cell Breast Epithelial Cells Breast cancer metastasis Carcinoma Cartilage Cell surface Cells Chemoresistance Clinical Complex Data Detection Development Diagnostic Disparity Doxycycline Epithelium Event Extracellular Matrix Foundations Frequencies Funding Generations Genetic Transcription Goals Growth HMGA2 gene Histologic Histopathology Human In Vitro Inbred BALB C Mice Invaded Investigation Knock-out Knockout Mice Laboratories Ligands Link Malignant Epithelial Cell Mammary Gland Parenchyma Mammary Neoplasms Mediating Mesenchymal Metaplastic carcinoma of the breast Modeling Molecular Morphology Mouse Mammary Tumor Virus Mus Mutate Mutation Neoplasm Metastasis Nuclear Oncogenic Organoids Pathologic Pathway interactions Patients Phenotype Productivity Prognosis Proteins Race Reagent Reporting Research Personnel Risk Role Signal Transduction TP53 gene Testing Tissue Sample Tissues Translating Tumor Suppressor Proteins Up-Regulation WISP3 gene WNT Signaling Pathway Woman Women&apos s Health Work beta catenin cancer subtypes cancer type cell motility clinical application clinical prognostic cohort diagnostic biomarker epithelial to mesenchymal transition extracellular follow-up health disparity human disease in vivo innovation insight knowledge integration malignant breast neoplasm mammary epithelium mouse model neoplastic novel diagnostics potential biomarker specific biomarkers stem-like cell therapeutic target translational impact translational study triple-negative invasive breast carcinoma tumor

项目摘要

Metaplastic breast carcinomas (mBrCAs) are a subset of triple negative breast cancer (TNBC) that occurs with higher frequency in African and African-American (AA) women, have histological evidence of epithelial-to-mesenchymal transition (EMT), and poor prognosis compared with other TNBC. mBrCAs consisting of spindle cells are the most frequent and the most lethal subtype. In humans TP53 is mutated with similar frequency in mBrCAs and in non-metaplastic TNBC (60-80% of cases). At present, the defining molecular alterations of mBrCAs are far from understood, and the 5-year overall survival for patients with mBrCA is 54% compared to 73% for TNBC. Our lab has discovered that CCN6 protein is reduced in 68% of human mBrCAs compared to 33% of other breast cancer types (p<0.02). A major breakthrough in our lab during the previous cycle has been the generation of a mammary epithelial cell-specific Ccn6 knockout mouse model that demonstrates a tumor suppressor function for Ccn6 in mBrCAs. All mammary tumors in MMTV-Cre;Ccn6fl/fl mice resemble human spindle mBrCAs morphologically and at the transcriptional level, and they share increased nuclear localization of beta-catenin in 78% of tumors, and increased expression of the canonical Wnt target genes HMGA2 and IMP2 (IGF2BP2). Since the initial submission, we have discovered that extracellular CCN6 antagonizes the effect of Wnt ligands on beta-catenin activation in vivo and in vitro, but the mechanisms, cooperating events, and functional consequences need further investigation. Our CENTRAL HYPOTHESIS is that loss of CCN6 expression is required to drive spindle mBrCAs, at least in part by enhancing Wnt/beta-catenin mediated activation of pro-invasive and pro- metastatic targets, such as HMGA2 and IMP2, and that detection of CCN6, beta-catenin, HMGA2, and IMP2 proteins may serve as specific biomarkers of mBrCA in clinical tissue samples, with diagnostic and treatment utility. We propose three independent and complementary specific aims: AIM 1. To investigate the consequences of inducible mammary epithelial cell-specific Ccn6 knockout as a driver of the unique spindle mBrCA phenotype, and to investigate the cooperation with p53. AIM 2. To elucidate the molecular mechanism(s) by which CCN6 suppresses progression of spindle mBrCAs in vivo and in vitro. AIM 3. To evaluate the translational impact of CCN6, beta-catenin, HMGA2, and IMP2 in breast tissue samples of African, AA, and Whites. We have developed a unique mouse model and have characterized cohorts of human breast cancer tissues (n>4,000, including 200 from Ghanaian, and 275 cases of mBrCAs of all races) with clinical information and >15 years of follow-up. We have generated critical preliminary data, which provide a strong scientific premise. The reagents and expertise are in place in the PI and co- Investigator's laboratories. Our innovative studies are expected to provide insights into new diagnostic markers and therapeutic targets for this aggressive subtype of TNBC, which are currently nonexistent.

化生性乳腺癌 (mBrCA) 是三阴性乳腺癌 (TNBC) 的一个子集，发生于在非洲和非裔美国人 (AA) 女性中发生率较高，有组织学证据上皮间质转化（EMT），与其他 TNBC 相比预后较差。 mBrCAs 由梭形细胞组成是最常见和最致命的亚型。在人类中 TP53 发生突变 mBrCA 和非化生性 TNBC 中的发生率相似（60-80% 的病例）。目前，定义 mBrCA 的分子改变尚不清楚，并且 mBrCA 患者的 5 年总生存率 mBrCA 为 54%，而 TNBC 为 73%。我们实验室发现CCN6蛋白减少了68% 人类 mBrCA 的比例与其他乳腺癌类型的 33% 相比 (p<0.02)。我们的重大突破实验室在上一个周期中已经产生了乳腺上皮细胞特异性 Ccn6 敲除小鼠模型展示了 mBrCA 中 Ccn6 的肿瘤抑制功能。所有乳腺肿瘤 MMTV-Cre;Ccn6fl/fl 小鼠在形态学和转录水平上类似于人纺锤体 mBrCA，它们在 78% 的肿瘤中都有增加的 β-连环蛋白核定位，并且表达增加典型的 Wnt 靶基因 HMGA2 和 IMP2 (IGF2BP2)。自初次提交以来，我们已经发现细胞外 CCN6 拮抗 Wnt 配体对体内 β-catenin 激活的影响和体外，但机制、合作事件和功能后果需要进一步研究调查。我们的中心假设是 CCN6 表达缺失是驱动纺锤体所必需的 mBrCA，至少部分是通过增强 Wnt/β-catenin 介导的促侵袭和促侵袭的激活来实现的。转移靶标，例如 HMGA2 和 IMP2，以及 CCN6、β-连环蛋白、HMGA2 和 IMP2蛋白可作为临床组织样本中mBrCA的特异性生物标志物，具有诊断和诊断作用。治疗效用。我们提出三个独立且互补的具体目标： AIM 1. 调查诱导性乳腺上皮细胞特异性 Ccn6 敲除作为独特驱动因素的后果纺锤体 mBrCA 表型，并研究与 p53 的配合。目的 2. 阐明分子 CCN6 在体内和体外抑制纺锤体 mBrCA 进展的机制。目标 3. 至评估 CCN6、β-连环蛋白、HMGA2 和 IMP2 在乳腺组织样本中的翻译影响非洲人、AA 人和白人。我们开发了一种独特的小鼠模型，并表征了人类乳腺癌组织（n>4,000，其中 200 例来自加纳，275 例 mBrCA）种族）以及临床信息和超过 15 年的随访。我们已经生成了关键的初步数据，提供了强有力的科学前提。 PI 和 co- 中的试剂和专业知识已到位研究人员的实验室。我们的创新研究有望为新的诊断提供见解这种侵袭性 TNBC 亚型的标志物和治疗靶点目前尚不存在。

项目成果

期刊论文数量（46）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Spatiotemporal analysis of glioma heterogeneity reveals COL1A1 as an actionable target to disrupt tumor progression.

DOI：
10.1038/s41467-022-31340-1
发表时间：
2022-06-24
期刊：
Nature communications
影响因子：
16.6
作者：
通讯作者：

Next-Gen Sequencing Exposes Frequent MED12 Mutations and Actionable Therapeutic Targets in Phyllodes Tumors.

DOI：
10.1158/1541-7786.mcr-14-0578
发表时间：
2015-04
期刊：
Molecular cancer research : MCR
影响因子：
0
作者：
Cani AK;Hovelson DH;McDaniel AS;Sadis S;Haller MJ;Yadati V;Amin AM;Bratley J;Bandla S;Williams PD;Rhodes K;Liu CJ;Quist MJ;Rhodes DR;Grasso CS;Kleer CG;Tomlins SA
通讯作者：
Tomlins SA

Matricellular CCN6 (WISP3) protein: a tumor suppressor for mammary metaplastic carcinomas.

基质细胞 CCN6 (WISP3) 蛋白：乳腺化生性癌的肿瘤抑制因子。