CAV-1 Epithelial-Stromal Interactions and Breast Cancer

描述(由申请人提供)：这项建议的长期目标是了解小窝蛋白-1在乳腺肿瘤发生(也称为肿瘤微环境)过程中，在乳腺上皮-间质相互作用中的作用。在这里，我们将研究Cav-1基因缺失小鼠乳腺上皮细胞增殖的发展。更具体地说，我们将机械地剖析上皮细胞或非上皮细胞对这种增生性Cav-1缺失表型的个体贡献。利用体外和体内乳腺重建实验，我们将探索Cav-1在乳腺上皮细胞或非上皮细胞(即间质细胞，包括成纤维细胞和脂肪细胞)中的特异性丢失是否都有助于上皮细胞增殖和肿瘤发生的失调。该项目的两个特定目标(SA)是：SA1)研究Cav-1在乳腺肿瘤发生过程中上皮-间质相互作用中的作用。为此，我们将通过乳腺重建实验，探索乳腺上皮细胞或非上皮细胞(即间质细胞，包括成纤维细胞和脂肪细胞)中Cav-1的特异性丢失是否都有助于上皮细胞增殖、增殖和肿瘤发生的失调。将对人类乳腺癌样本进行进一步的研究，以确定乳腺基质细胞中的CAV-1突变。SA2)探讨Cav-1表达在Cyclin D1诱导的乳腺肿瘤发生中的作用。在这一目标中，我们将通过将Cav-1(-/-)空载体和Cav-1转基因(TG)小鼠与MMTV-Cyclin D1转基因小鼠杂交，来评估Cav-1的表达如何调控Cyclin D1诱导的乳腺肿瘤发生。将进行补充实验，使用基于细胞渗透性小窝蛋白-1的模拟多肽的治疗性给药。在此背景下，还将评估上皮-间质的贡献。这些研究将有助于了解Cav-1在乳腺细胞转化和肿瘤发生过程中调节上皮-间质相互作用的作用。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand the role of caveolin-1 in mammary epithelial-stromal interactions, during mammary tumorigenesis (a.k.a., the tumor microenvironment). Here, we will investigate the development of epithelial cell hyperplasia in the mammary glands of Cav-1 null mice. More specifically, we will mechanistically dissect the individual contributions of epithelial or non-epithelial cells to this hyperplastic Cav-1 null phenotype. Using both in vitro and in vivo mammary reconstitution experiments, we will explore whether the specific loss of Cav-1 within mammary epithelial cells or non-epithelial cells (i.e. stromal cells, including fibroblasts and adipocytes) both contribute to a dysregulation of epithelial proliferation and tumorigenesis. The two Specific Aims (SAs) of the project are: SA1) To examine the role of Cav-1 in epithelial-stromal interactions during mammary tumorigenesis. For this purpose, we will explore whether the specific loss of Cav-1 within mammary epithelial cells or non-epithelial cells (i.e. stromal cells, including fibroblasts and adipocytes) both contribute to a dysregulation of epithelial cellular proliferation, hyperplasia, and tumorigenesis, using mammary reconstitution experiments. Additional studies will be carried out with human breast cancer samples to identify CAV-1 mutations in mammary stromal cells. SA2) To determine the effects of Cav-1 expression on Cyclin D1-induced mammary tumorigenesis. In this aim, we will evaluate how Cav-1 expression modulates Cyclin D1-induced mammary tumorigenesis, by crossing Cav-1 (-/-) null and Cav-1 transgenic (Tg) mice, with MMTV-Cyclin D1 transgenic mice. Complementary experiments will be carried out employing the therapeutic administration of a cell permeable caveolin-1-based mimetic peptide. In this context, epithelial-stromal contributions will also be evaluated. These studies will contribute fundamental knowledge toward understanding the role of Cav-1 in regulating epithelial-stromal interactions, during mammary cell transformation and tumorigenesis.