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    Research Grants Awarded

    Targeting STAT1 in the Treatment of Breast Cancer

    Study Section:

    Scientific Abstract:
    Given the limited progress that has been made in treating advanced breast cancer with non-specific cytotoxic drugs, it is clear that more rational strategies will be required. The next generation of treatments for patients with this disease will likely be centered on targeted therapies based on an enhanced understanding of the molecular abnormalities in breast cancer cells. Recently it has been found that the transcription factor STAT1 plays an important role in suppressing the malignant behavior of tumor cells, and in mediating the apoptotic response to cytotoxic chemotherapy. Furthermore, we have found that amplification of the transmembrane receptor tyrosine kinase Her2 (ErbB2), which leads to a more aggressive behavior of tumors, also leads to suppression of STAT1 levels. Notably, inhibitors of the signaling molecule mTOR can reverse this repression, indicating that it may be amenable to therapeutic modulation. To exploit the important role of STAT1, both as a tumor suppressor and as a mediator of the therapeutic effects of chemotherapy, we developed a high throughput screening system to isolate STAT1 enhancers. Using this approach, we have identified 2-(1,8-Naphthyridin 2-yl)phenol (2-NP) as a potent and specific enhancer of STAT1 function. Building on this preliminary work, we now propose to elucidate the mechanism by which STAT1 functions in breast cancer biology, and to critically test the hypothesis that enhancing STAT1 function will accentuate the killing of breast cancer cells for therapeutic purposes. To do this, we will focus on three specific aims: (1) To identify how specific target genes mediate the tumor suppressive effects of STAT1; (2) To discern the mechanism by which Her2 amplification represses STAT1 expression; and, (3) To analyze the role of 2-NP in enhancing the sensitivity of breast cancer cells to therapy. As a result of these experiments, we will have a greater insight into the role that STAT1 plays in breast cancer biology and therapy, and we will be able to develop specific therapeutic strategies that can be translated into clinical trials for patients with advanced breast cancer.

    Lay Abstract:
    The cornerstone of therapy for patients with advanced breast cancer is the use of drugs that kill cells in an indiscriminate manner. As a result, these agents are fairly toxic, and provide meaningful benefit to a minority of breast cancer patients. A new generation of anti-cancer agents can be developed by focusing on particular molecular pathways operating in breast cancer cells, and exploiting these in a targeted fashion. It has been found that a cellular protein called STAT1 is an important internal control on the aggressive behavior of cells, and also is involved in mediating the killing of breast cancer cells following chemotherapy. In addition, we have found that STAT1 levels are suppressed in a highly malignant form of breast cancer, in which a particular protein called Her2 is expressed in excess. We have also uncovered strategies by which this suppression can be reversed, and we have identified a drug that can enhance the activity of STAT1 in breast cancer cells. Based on these findings, we now propose to critically determine the role that STAT1 plays in breast cancer biology and to delineate how the drugs we have identified can be used to accentuate the specific killing of breast cancer cells. As a result of this work, we will not only enhance our understanding of a fundamental aspect of the biology of breast cancer cells, but we will also develop specific strategies by which this new targeted molecular approach can be used to improve the treatment of women with this disease.