Profilin biology in breast cancer

乳腺癌是女性最常见的非皮肤癌，在 美国女性癌症死亡人数。这些死亡中的绝大多数是由于 转移。肌动蛋白调节蛋白的异常表达和/或活性导致 能使乳腺癌细胞转移扩散的能动表型。这样做的目的是 这项研究是为了获得对profilin1的基本机械见解，profilin1是肌动蛋白的主要调节因子 细胞骨架，影响膜-胞质界面的细胞信号，这些信号对 乳腺癌转移的早期步骤。我们在该项目中提出了两个具体目标。在目标1中， 我们将阐明Profilin 1‘S与细胞膜结合是如何改变细胞膜磷脂酰肌醇的 细胞内的动力学。在目标2中，我们将进一步建立Profilin1-之间的因果联系 膜上肌醇磷脂信号的依赖性调节及肌醇磷脂介导 促迁移信号轴在调控乳腺癌细胞转移转移中的作用 原发肿瘤。这些研究将利用一种综合的实验方法，结合高度和 脂质生物传感器的分辨率活细胞成像，膜扩散动力学的成像 单分子水平的蛋白质、癌细胞扩散的活体成像和临床 样本分析。这项研究的成功完成将为乳房提供新的机制 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.