GENETIC ALTERATION IN EPITHELIAL AND STROMAL COMPARTMENT OF BREAST ADENOCARCINOMA

大多数乳腺癌是散发性的，但大约5%-10%是遗传性的。尽管知道微环境在肿瘤发展中的重要性，但迄今为止，对实体肿瘤的遗传学研究，无论是散发性的还是遗传性的，都将它们视为单一的无定形实体。乳房腺癌的基因分析也不例外。我们有散发性人类乳腺癌的初步杂合性缺失(LOH)和体细胞TP53/PTEN突变数据，这表明基因改变可以不同地发生在肿瘤上皮室以及周围的间质室中。我们假设，肿瘤微环境，特别是间质间隔，在乳腺癌的发生中扮演着重要的角色，尽管在很大程度上没有明确的定义，无论是在零星的情况下还是在遗传的情况下。 这项应用将使用遗传学方法来解决这一假设，即乳腺癌间质和上皮室的LOH对肿瘤生长有不同的贡献，因此它们对临床结果的影响是不同的。因此，该项目将采用几种遗传学方法来研究肿瘤微环境在乳腺癌发展中的作用。首先，将通过全基因组杂合性缺失以及通过激光捕获显微切割(LCM)获得的模板细胞的PTEN和TP53突变分析来评估225例人类乳腺肿瘤样本上皮和间质细胞间的遗传变化。 此外，在同一大系列乳腺癌的上皮和间质成分中的这些体细胞遗传改变将与临床结果相关。其次，将建立一个小鼠模型来研究乳腺癌发生中上皮-间质相互作用的问题，特别是靶向干扰Pten，它被认为参与了遗传性和散发性人类乳腺癌的发生。 使用cre-loxP技术的靶向破坏Pten将分别在上皮和间质中进行，并分析各自的后果。在未来，计划项目中开发的每一种小鼠模型下游的乳腺肿瘤间质和上皮组织中的遗传变化的检查是被设想的。因此，该项目的目标是在临床和分子水平上阐明相关的间充质(间质)-上皮相互作用，这些相互作用影响肿瘤细胞的细胞周期、凋亡和侵袭性的控制。这些可能对临床治疗或预防的靶向有未来的影响。

Most breast cancers are sporadic but approximately 5-10% are hereditary. Despite knowing the importance of the role of the microenvironment in tumor development, genetic studies of solid tumors, whether sporadic or hereditary, to date, have treated them as single amorphous entities. Genetic analyses of adenocarcinomas of the breast are no exception. We have preliminary loss of heterozygosity (LOH) and somatic TP53/PTEN mutation data in sporadic human breast cancer, which demonstrates that genetic alterations can differentially occur in the neoplastic epithelial compartment as well as the surrounding stromal compartment. We hypothesize that the tumor microenvironment, especially the stromal compartments, play an essential, albeit largely undefined role, in breast carcinogenesis, whether in the sporadic setting or in the hereditary setting. This application will use a genetic approach to address the hypothesis that LOH in the stromal and epithelial compartments of breast adenocarcinomas differentially contribute to tumor growth, such that they affect clinical outcomes differently. Thus, this project will take several genetic approaches to study the role of the tumor microenvironment in breast cancer development. First, genetic alterations in the epithelial and stromal cellular compartments of 225 human breast tumor samples will be assessed by genome-wide LOH as well as PTEN and TP53 mutation analyses on template cells obtained by laser-capture microdissection (LCM). Further, these somatic genetic alterations in the epithelial and stromal components of this same large series of breast cancers will be correlated with clinical outcomes. Second, a murine model will be developed to examine the issue of epithelial-stromal interaction in mammary carcinogenesis, specifically, targeted disruption of Pten, which is known to participate in inherited and sporadic human breast carcinogenesis. Targeted disruption of Pten, using cre-loxP technology, will be performed separately in the epithelium and in the stroma and the consequences of each analyzed. In the future, examination of genetic alterations in the mammary neoplastic stroma and epithelium downstream of each of the mouse models developed in the Program Project is envisioned. Thus, the goals of the proposed project are to elucidate, at the clinical and molecular level, the relevant mesenchymal (stromal)-epithelial interactions, which impact on the control of the cell cycle, apoptosis and invasiveness of tumor cells. These might have future implications for clinical targeting for therapy or prevention.