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    Wip1 As A Novel Therapeutic Target For Human Breast Cancer

    Scientific Abstract:
    Wip1 As A Novel Therapeutic Target For Human Breast Cancer (BCTR0504146). BACKGROUND: Overexpression of a wild type p53-inducible serine/threonine protein phosphatase, Wip1, (also know as PPM1D), through gene amplification has recently been found in 16% of human breast tumor tissue samples. The Wip1 gene is located in the 17q23 amplicon, a novel region of amplification in breast tumor that has been linked to a poor prognosis in breast cancer patients. Overexpressed Wip1 can expedite tumor formation in cooperation with an activated H-ras or Her-2/neu oncogene both in vitro and in vivo. However, it is not yet know whether overexpression of Wip1 by itself contributes to the formation of mammary tumors. Our HYPOTHESIS is that overexpression of Wip1 contributes to human breast cancer development and drug resistance. To test this, three SPECIFIC AIMS are proposed: 1. To determine if overexpression of Wip1 results in the formation of mammary tumors in vivo. 2. To test if reducing Wip1 expression can reduce the tumorigenicity and increase the sensitivity to therapeutics of human breast cancer cell lines that overexpress Wip1. 3. To assess if knockdown Wip1 expression will translate into a therapy in an orthotopic human breast xenograft model. STUDY DESIGN: In order to determine if Wip1 overexpression can result in the formation of mammary tumors in vivo, we will generate transgenic mice expressing Wip1 in the mammary epithelium under the transcriptional control of the mouse mammary tumor virus (MMTV) long terminal repeat (LTR). To test if reducing Wip1 expression can reduce tumorigenicity and enhance the sensitivity to therapeutics, we will use a small interfering RNA (siRNA) approach to generate derivatives of Wip1-overexpressing human breast cancer cell lines that express reduced levels of Wip1. The tumorigenicity and sensitivity to therapeutics of each parental cell line and its derivatives will then be compared. To test if we could translate this as a therapy to treat breast cancer, orthotopic human breast xenografts in nude mice will be treated with chemotherapy alone or chemotherapy plus Wip1 siRNA by a systemic delivery. POTENTIAL OUTCOMES AND BENEFITS OF THE RESEARCH: The proposed study will determine whether overexpression of Wip1 results in the formation of mammary tumors in vivo and whether reducing Wip1 level decreases the tumorigenicity and/or increases the sensitivity to therapeutics of human breast cancer cell lines that overexpress Wip1. Thus, the finding of this study could potentially translate into more effective treatments of human breast cancer.

    Lay Abstract:
    Wip1 As A Novel Therapeutic Target For Human Breast Cancer (BCTR0504146). Breast cancer is the most common cancer in women worldwide and accounts for one sixth of cancer death in the United States. Significant progress has been made in understanding the biology of breast cancer and in developing new therapies based on this knowledge in the last two decades. However, there is still much to be learned about how breast cancers develop and how to improve the therapeutic efficacy. In addition, there is still a great need for innovative and rationally designed, mechanism-based approach for the treatment of breast cancer. The Wip1 gene is located in the chromosome 17q23 and amplification of 17q23 has been linked to a poor prognosis in breast cancer patients. The overexpression of Wip1 protein has been found in 16% of primary breast tumors. In addition, studies have shown that overexpression of Wip1 repressed a key tumor suppressor p53 functional activation and expedite tumor formation in vivo, while mouse embryo fibroblast deprived Wip1 expression had a reduced growth rate and enhanced p53 functional activity. These findings strongly suggest that high levels of Wip1 contribute to the development of breast cancer and Wip1 may provide a clinically important target for the development of anticancer therapeutics. Thus, reducing the Wip1 level may be a way to reduce the aggressiveness of breast tumors that contain high level of this protein. In addition, reducing the Wip1 level might also make such tumors more sensitive to therapeutics. Our proposed study is designed to find out whether reducing the Wip1 level in breast tumors with high level of this protein makes these tumors less aggressive but more sensitive to therapeutics. Our findings may lead to better understanding of how breast cancer develops and could result in new treatments for breast cancer.