Profilin biology in breast cancer

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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.