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    Research Grants Awarded

    Estrogen Receptor -Tumor Suppressor p53 Interaction: A Basis for Novel Therapeutic Strategies against Breast Cancer

    Study Section:
    Tumor Cell Biology II

    Scientific Abstract:
    Background: It is well documented that estrogen receptor alpha (ERa) and p53 tumor suppressor protein play important roles in normal breast development and function as well as in the onset and progression of breast cancer. However, whether there is a direct link between these two antagonistic pathways is not known. While addressing this important issue, we have discovered a novel function of ERa: it can antagonize p53 tumor suppressor function by direct interaction. Objective/Hypothesis: Based on our data, I hypothesize that ERa antagonism toward p53 plays a major role in breast oncogenesis. Further, based on our observation that radiation and drugs such as tamoxifen and fulvestant can disrupt the ERa-p53 interaction and our clinical observation that p53 is associated with better response to tamoxifen therapy in breast cancer patients, I propose to investigate the mechanism of ER-p53 interaction and disruption as well as its consequences in human breast cancer cells. Specific Aims: (1) Delineate domains required for ERa-p53 interaction and analyze the mechanism of interaction and disruption of interaction (2) Analyze the effect of 17-b estradiol, tamoxifen, fulvestrant (ICI 182780), and adraimycin on ERa-p53 interaction and subsequent cellular effects in the absence and presence of radiation in cells with or without HER2 over-expression. (3) Investigate the effect of ERa-p53 interaction on tumor growth of MCF7 breast cancer cell xenograft in mice. Study Design: We will analyze ER-p53 interaction in MCF-7 human breast cancer cells that have both wild type ER and p53. We will use RNAi technology to knockdown ERa and p53 separately in breast cancer cells followed by chromatin immunoprecipitation ChIP) assays and quantitative real time PCR, and transfection assays to analyze the interaction and its functional consequences under various conditions. Effect on cell cycle arrest and apoptosis will be investigated. The cellular studies will be complemented with xenograft studies. Potential outcomes and Benefits of the Research: The proposed experiments could provide important insight into why wild type p53 cannot exert its tumor suppressive function in ER-positive tumors. Further, this study looking at ER function from a novel angle should shed light on the complex issue of resistance to tamoxifen and may help to formulate new therapeutic and preventive strategies.

    Lay Abstract:
    Background: Estrogen receptor (ER) plays an important role in stimulation of breast cancer development by estrogen. p53 tumor suppressor protein, on the other hand, is a negative regulator of cell proliferation. However, whether there is a direct link between these two antagonistic pathways is not known. While addressing this important issue, we have discovered that ER represses p53 tumor suppressor function by direct interaction. Our clinical data on breast cancer patients are consistent with this cellular and molecular data. Objective/Hypothesis: Based on our data, I hypothesize that ER antagonism toward p53 plays a major role in breast oncogenesis. Further, based on our observation that radiation and drugs such as tamoxifen and fulvestrant can disrupt the ER-p53 interaction and our clinical observation that presence of normal (wild type) p53 in tumors enhances response to tamoxifen therapy in breast cancer patients, I propose to investigate the mechanism of ER-p53 interaction and disruption as well as its consequences in human breast cancer cells. Specific Aims: The first specific aim will analyze the regions of ER and p53 required for interaction. The second specific aim will address the effects of estrogen and breast cancer drugs tamoxifen, fulvestrant, and adriamycin (doxorubicin) on interaction between ER and p53 in the absence and presence of radiation and their physiological consequences in breast cancer cells. We will also investigate whether HER2 over expression alters the effect of radiation or antihormonal drugs on ER-p53 interaction. Under the third specific aim, we propose to grow human breast cancer cells in mice (xenograft) for analyzing the effects of ER-p53 interaction on tumor growth and response to tamoxifen and radiation therapies. Study Design: We will use state-of-the-art cellular and molecular biological techniques to analyze ER-p53 interaction and its functional consequences under various conditions including selective knock down of ER or p53 in MCF-7 human breast cancer cells. The cellular studies will be complemented with xenograft studies. Potential outcomes and Benefits of the Research: The proposed experiments could provide important insight into why normal p53 cannot exert its tumor suppressive function in ER-positive tumors. Further, this study on ER and p53 function from a novel angle should shed light on the complex issue of resistance to tamoxifen and may help to formulate new therapeutic and preventive strategies.