Profilin biology in breast cancer

乳腺癌是女性中最常见的非皮肤癌， 美国女性的癌症死亡率。这些死亡中的绝大多数是由于 转移肌动蛋白调节蛋白的表达和/或活性失调有助于 能够转移乳腺癌细胞的运动表型。这个目标 这项研究的目的是获得基本的机制见解，了解肌动蛋白的主要调节因子profilin 1 细胞骨架，影响细胞信号在膜-胞质溶胶界面，这是重要的 乳腺癌转移的早期步骤。我们在项目中提出了两个具体目标。在目标1中， 我们将阐明profilin 1与细胞膜的结合如何改变膜磷酸肌醇 细胞中的动力学在目标2中，我们将进一步建立profilin 1- 膜磷酸肌醇信号传导的依赖性调节和磷酸肌醇指导的 促迁移信号轴在调节乳腺癌细胞转移性扩散中的作用 原发性肿瘤这些研究将采用综合实验方法，结合高- 脂质生物传感器的分辨率活细胞成像， 单分子水平的蛋白质，癌细胞播散的活体成像和临床 样品分析这项研究的成功完成将为乳腺癌的发生提供新的机制。 癌症扩散。

Breast cancer the most frequently diagnosed non-skin cancer in women, ranks second among cancer deaths in women in the United States. The vast majority of these deaths are due to metastasis. Dysregulated expression and/or activity of actin-regulatory proteins contribute to the motile phenotype that enables metastatic dissemination of breast cancer cells. The goal of this study is to gain fundamental mechanistic insights into how profilin1, a major regulator of actin cytoskeleton, influences cell signaling at the membrane-cytosol interface that are important for early steps of breast cancer metastasis. We propose two specific aims in the project. In Aim 1, we will elucidate how profilin1’s binding to cell membrane alters membrane phosphoinositide dynamics in cells. In aim 2, we will further establish a causal connection between profilin1- dependent modulation of membrane phosphoinositide signaling and phosphoinositide-directed pro-migratory signaling axis in regulating metastatic dissemination of breast cancer cells from the primary tumor. These studies will utilize a comprehensive experimental approach combining high- resolution live cell imaging of lipid biosensors, imaging of membrane diffusion dynamics of proteins at the single molecule level, intravital imaging of cancer cell dissemination and clinical sample analyses. A succesful completion of this study will provide novel mechanisms for breast cancer dissemination.