The Role of Syndecan-1 in Mouse Mammary Neoplasia

在我们的第一项资助中，我们提供了异位Wnt信号通过干细胞祖细胞诱导乳腺肿瘤的证据。 细胞前体这很可能是一个更大的一类肿瘤的先驱与不同的病因。 因此，从治疗患有在干细胞区室中产生的肿瘤的人类患者（如， 慢性粒细胞白血病）已经表明，有效的治疗策略需要潜在的干细胞 细胞生物学有待分析和理解。我们建议通过研究Sdc 1-/-小鼠，我们将能够 表征使茎-祖细胞隔室易于转化的特征。我这样 发现这些小鼠对靶向干祖细胞的癌基因的肿瘤发展有抵抗力 细胞（乳腺中对Wnt效应物的反应）和对致癌物的反应（所有 肿瘤的主要类型）。我们将特别关注分析致癌物诱导的肿瘤，因为这些 (like Wnt诱导的肿瘤）具有与干细胞前体相关的标志，并且可能具有 与人类乳腺癌直接相关。尽管Sdc 1-/-小鼠只有少量的干祖细胞 在乳腺和造血谱系中，它们的干细胞活性低。在这里，我们测试 假设Sdc 1-/-体干细胞谱系活性不足，这赋予了它们的抗性 致癌物。我们将测试Sdc 1-/-乳腺干细胞活性缺陷的性质， 干祖细胞对致癌物的管理，致癌物诱导的肿瘤的起源， Sdc 1缺失引起的缺陷的分子基础。这种缺陷不仅适用于乳腺癌， 和造血谱系，但许多其他，包括造血干细胞和实体器官， 肺和肝。通过了解这些小鼠的缺陷，我们的目标是找出当体干细胞 车厢容易转变，什么因素调节这一过程。

In our first grant, we provided evidence that ectopic Wnt signaling induces breast tumors via a stemprogenitor cell precursor. This is likely to be a forerunner of a larger class of tumors with a different etiology. Thus, experience gained from treating human patients with tumors arising in the stem cell compartment (like chronic myelogenous leukemia) has shown that effective therapeutic strategies require the underlying stem cell biology to be analyzed and understood. We propose that by studying Sdc1-/- mice, we will be able to characterize features that make a stem-progenitor compartment vulnerable to transformation. Thus we have found that these mice are resistant to tumor development in response to oncogenes that target stemprogenitor cells (in mammary gland in response to Wnt effectors) and in response to carcinogens (in all major classes of tumors). We will focus particularly on analyzing carcinogen-induced tumors, since these (like Wnt-induced tumors) have the hallmarks associated with a stem cell precursor, and are likely to have direct relevance to human breast cancer. Although Sdc1-/- mice have only marginally depleted stemprogenitor number in mammary arid hematopoietic lineages, they have low stem cell activity. Here, we test the hypothesis that Sdc1-/- somatic stem cell lineages are underactive, and that this confers their resistance to carcinogens. We will test the nature of the defect in Sdc1-/- mammary stem cell activity, the reaction of stem-progenitor cells to carcinogen administration, the origins of carcinogen-induced tumors, and the molecular basis of the defect induced by the absence of Sdc1. This defect may apply not only to mammary and hematopoietic lineages but to many others, including hematopoietic stem cells and solid organs such as lung and liver. By understanding the defects in these mice we aim to find out when somatic stem cell compartments are prone to transformation, and what factors regulate this process.