The Role of Syndecan-1 in Mouse Mammary Neoplasia

描述（由申请人提供）：有一类乳腺肿瘤的预后明显差于其他肿瘤，即所谓的三阴性肿瘤（ER-ve、PR-ve、HER2-）。他们预后不良的一个原因是缺乏靶向治疗（他们对他莫昔芬或赫赛汀无反应）。在这个应用中，我们假设致癌物诱导的小鼠乳腺肿瘤是一个很好的三阴性乳腺癌模型。通过转录谱分析，它们聚集在一个小鼠亚组（包括来自BRCA1、p53和Wnt转基因小鼠的肿瘤）中，与来自女性的三阴性basaloid组的特征相似。他们有双管分化的标记，这意味着癌症干细胞的存在。在文献中，有一些数据表明，其他类型的癌症干细胞对标准的化疗和放疗策略相对耐药，这可能是肿瘤复发或无反应性的原因。该应用程序旨在解决该领域的一个经典难题，即肿瘤前体细胞是否来自乳腺中的正常干细胞。如果对募集过程有了更好的了解，就有可能不仅了解如何防止前体转化，而且还可能了解癌症干细胞是否与正常干细胞共享更多特性（或者仅仅获得一种赋予不朽生长潜力的特定功能）。一种具有硫酸肝素蛋白多糖突变等位基因syndecan1 （Sdc1）的特定小鼠品系，对致癌物和癌基因诱导的肿瘤具有显著的抗性，并且被怀疑在干细胞/祖细胞的致病性激活中存在关键缺陷。因此，这种小鼠品系代表了一种工具，可以帮助确定癌症起始的高度易感阶段。在这项应用中，目标包括阐明致癌物诱导肿瘤的起源（使用基于发现LRP5作为乳腺干细胞生物标志物而新开发的小鼠品系），发现Sdc1-/-小鼠肿瘤保护的细胞机制，描述干细胞、祖细胞和分化细胞组分对遗传毒性致癌物的特异性反应，并阐明了它们抵抗肿瘤发展的分子途径。目前，人们还不完全了解引发这种肿瘤过程的起始事件，对这种小鼠品系的分析代表了一个独特的发现机会。公共卫生相关性：一种特殊的小鼠品系（携带syndecan-1基因突变，一种细胞表面硫酸肝素蛋白多糖）对致癌物治疗后产生的肿瘤具有显著的耐药性。有证据表明，这些肿瘤的前体细胞起源于正常的干细胞室，并发生突变成为“癌症干细胞”。分析这些小鼠乳腺组织在致癌物给药期间的反应，可以确定调节乳腺干细胞向肿瘤募集的因素，并为如何减少致癌物暴露后的肿瘤负荷提供建议。

DESCRIPTION (provided by applicant): There are a group of breast tumors that have a significantly worse prognosis than the others, the so-called triple negative tumors (ER-ve, PR-ve, HER2-). One reason for their poor prognosis is a lack of targeted therapies (they are non-responsive to tamoxifen or herceptin). In this application, it is postulated that carcinogen-induced breast tumors in mice are a good model of triple negative breast cancer. By transcriptional profiling, they cluster in a mouse subgroup (including tumors from BRCA1, p53 and Wnt transgenic mice) that resembles the profile of basaloid, triple negative group from women. They have markers of bilineal differentiation, which implies the presence of a cancer stem cell. In the literature, there is some data to suggest that other types of cancer stem cells are relatively resistant to the standard chemo- and radiotherapeutic strategies, and that this could be the reason for tumor recurrence or non- responsiveness. This application seeks to resolve a classic dilemma in this field, which is whether the tumor precursor cells are drawn from normal stem cells in the breast. If the process of recruitment is better understood, it may be possible to understand not only how to prevent precursor transformation, but also whether the cancer stem cells share more properties with normal stem cells (or have acquired just one specific function that confers immortal growth potential). A specific mouse strain with a mutant allele of a heparan sulfate proteoglycan, syndecan1 (Sdc1), is dramatically resistant to carcinogen- and oncogene- induced tumors and is suspected to have a key deficiency in the pathogenic activation of stem/progenitor cells. This mouse strain therefore represents a tool that can help to pinpoint a highly susceptible stage of cancer initiation. In this application, the Aims include the elucidation of the origin of carcinogen-induced tumors (using a newly developed mouse strain based on the discovery of LRP5 as a mammary stem cell biomarker), the discovery of the cellular mechanism of tumor protection in Sdc1-/- mice, a description of the specific response of stem, progenitor and differentiated cell fractions to genotoxic carcinogen administration, and the elucidation of the molecular pathways that underlie their resistance to tumor development. The initiating events that start this tumor process are currently not at all understood, and the analysis of this mouse strain represents a unique opportunity for discovery. PUBLIC HEALTH RELEVANCE: A specific strain of mouse (carrying a mutation in the syndecan-1 gene, a cell surface heparan sulfate proteoglycan) is dramatically resistant to tumors that develop after treatment with carcinogens. There is evidence to suggest that the precursor cells for these tumors originate in the normal stem cell compartment, and that they are mutated to become "cancer stem cells". Analysis of the response of breast tissue from these mice during carcinogen administration can pinpoint the factors that regulate the recruitment of mammary stem cells to tumors, and advise on how to reduce tumor load after carcinogen exposure.