Radiation therapy plays a critical role in the management of breast cancer and the sensitivity of the tumor cells to radiation is a critical determinant of the probability of local control and, ultimately, of cure. Tumors fail locally after radiation therapy due to alterations in the molecular pathways associated with the particular tumor. A variety of molecular factors are being used in clinical practice to predict the prognosis and response to radiation therapy of breast cancer patients. Unraveling the underlying mechanism controlling the development of resistance to radiation therapy can help delay onset or eliminate development of resistance and prolong treatment efficacy. HuR is an RNA binding protein, which functions to increase or decrease mRNA stability. Altering the subcellular distribution or expression of RNA binding proteins that alter mRNA stability has the potential to significantly alter levels of key growth promoting proteins. In this grant application we are proposing to test if cytoplasmic accumulation of the RNA binding protein-HuR in human breast cancer cells is a mechanism for the origin of radioresistant breast cancers. We believe that cytoplasmic HuR, through its interaction with stress activated signaling pathways and DNA repair proteins, functions to stabilize transcripts essential for cell survival and plays an important role in dictating radiation response. To address this, we propose the following specific aims:
Aim 1 : Investigate HuR expression levels in a panel of breast tumor and normal cell lines and study the effect of radiation on the subcellular distribution of HuR. Test the hypothesis that cytoplasmic HuR effects the MAPK and DNA repair proteins to modulate radiation resistance.
Aim 2 : Conduct in vitro and in vivo studies using HuR-targeted siRNA and determine the consequences of therapeutic intervention on modulation of radiation response and DNA repair.
Aim 3 : Generation of tissue arrays and immunohistochemical analysis on a cohort of human breast carcinomas to look for possible associations between radiation response and HuR expression and other clinicopathologic variables.
We hypothesize that a better understanding of the interactions between HuR, MAPK and DNA repair pathways will identify proteins responsible for sensitivity and resistance to ionizing radiation. Understanding these mechanisms will ultimately permit the optimal integration of new inhibitors into breast cancer therapy and ultimately overcome resistance and failure to radiation therapy.
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