Investigating the Role of Nuclear Clusterin (nCLU) in Lethality and Genomic Instability in Paclitaxel (Taxol) - Treated Human Breast Cancer Cells

摘要

Clusterin is a protein that has been implicated in many normal physiological processes (tissue remodeling, sperm maturation) as well as many pathological processes (Alzheimer disease, atherosclerosis, cancer). Our laboratory became interested in clusterin when we identified it as an x-ray induced protein/transcript in human melanoma cells. The secretory form of clusterin (sCLU) has been shown to have cytoprotective effects after cellular stress and injury. Recently, Redondo et. al demonstrated that sCLU was overexpressed in breast cancer. sCLU over expression may provide a selective advantage in malignant cells. The most effective therapies for breast cancer after surgery include chemo- and radiation therapies. These therapies often fail as the tumor develops drug and radiation resistance. Our lab has shown that sCLU is induced by physiological doses of taxol, taxotere and radiation. Additionally, we have shown that sCLU is transcriptionally repressed by the tumor suppressor protein, p53, which is found mutated in approximately 20% of mammary tumors. Understanding the cellular and molecular responses of malignant and normal cells to these chemo- and radiation therapy would allow us to increase the efficacy of these treatments. Insight into the regulation of sCLU will allow us to better understand some of these processes.