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作用的重要性，但迄今为止，实体瘤的遗传学研究，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。乳腺腺癌的基因分析也不例外。我们有初步的杂合性丢失（洛合性）和体细胞TP 53/PTEN突变的数据在散发性人乳腺癌，这表明，遗传改变可以差异发生在肿瘤上皮室以及周围的基质室。我们假设，肿瘤微环境，特别是间质区室，发挥了重要的，虽然在很大程度上不确定的作用，在乳腺癌的发生，无论是在散发设置或在遗传设置。 本申请将使用遗传学方法来解决乳腺腺癌的基质和上皮隔室中的洛合性缺失差异性地促进肿瘤生长的假设，使得它们不同地影响临床结果。因此，该项目将采取几种遗传方法来研究肿瘤微环境在乳腺癌发展中的作用。首先，225人乳腺肿瘤样本的上皮细胞和间质细胞区室的遗传改变将通过全基因组洛以及激光捕获显微切割（LCM）获得的模板细胞上的PTEN和TP 53突变分析进行评估。 此外，这些体细胞遗传改变的上皮和基质成分的这同一大系列的乳腺癌将与临床结果。其次，将开发小鼠模型来研究乳腺癌发生中上皮-基质相互作用的问题，特别是Pten的靶向破坏，已知Pten参与遗传性和散发性人类乳腺癌发生。 使用cre-loxP技术，将在上皮和基质中分别进行Pten的靶向破坏，并分析各自的后果。在未来，在乳腺肿瘤基质和上皮细胞下游的每一个小鼠模型中开发的程序项目的遗传改变的检查是设想。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（基质）-上皮相互作用，其影响肿瘤细胞的细胞周期、凋亡和侵袭力的控制。这些可能对临床靶向治疗或预防具有未来意义。

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.