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Role of Protein Kinase C delta in Mammary Gland Apoptosis and Tumorigenesis
Tumor Cell Biology V
Background: The ability to evade apoptosis is considered an essential “hallmark of cancer” and genetic disruption of the apoptotic pathway is an extremely common feature of breast and other epithelial tumors. Studies in transgenic and “knock-out” mice in which expression of specific components of the apoptotic pathway are altered indicate that genes involved in regulating apoptosis can function as tumor suppressors. PKC d is emerging as an essential component of the apoptotic pathway in epithelial cells. Using a PKC d knock-out mouse, we have shown that loss of PKC d results in suppression of apoptosis in mammary epithelial cells in vitro , and during mammary gland involution in vivo . PKC d also suppresses cell migration, suggesting that it may be important for inhibition of tumor metastasis. H ypothesis /O bjective : We hypothesize that PKCd functions as a tumor suppressor and that loss of PKC d will enhance mammary gland tumorigenesis and/or metastasis. Specific Aims: (1) To determine if loss of PKC d enhances/accelerates mammary gland tumorigenesis and/or metastasis in the HER2/c-neu mouse model of human breast cancer. (2) To explore the molecular mechanism(s) by which loss of PKC d contributes to mammary gland tumorigenesis. Study Design : In Aim 1 we will ask if the frequency of mammary gland tumors and/or tumor metastasis is increased in the PKC d knock-out mice and in PKC d knock-out mice crossed with HER2/c-neu transgenic mice as compared to control mice. In AIM 2, the molecular basis for enhanced tumorigenesis will be explored using three-dimensional cultures of primary mammary epithelial cells derived from wild type and PKC d knock-out mice. These cultures have been used previously to explore cell and tissue events involved in mammary gland development and neoplasia. Using this approach we will address the role of PKC d in mammary epithelial cell apoptosis, mammary tissue architecture and epithelial cell migration. To verify a role for PKCd in these processes, these studies will be repeated following reconstitution of mammary epithelial cells with PKC d by adenoviral transduction. Potential Outcome and Benefits of Research: Drugs which target the apoptotic pathways are likely to be clinically very important for breast and other types of cancer. Conceivably, pro-apoptotic drugs could be designed to induce apoptosis directly, or to increase the responsiveness of the apoptotic machinery to conventional therapeutic drugs.
BACKGROUND: Apoptosis is a specialized type of cell death that plays a critical role in eliminating damaged or genetically altered cells, including tumor cells. The ability to evade apoptosis is considered an essential “hallmark of cancer” and genetic disruption of the apoptotic pathway is an extremely common feature of breast and other tumor cells. Hypothesis : Using a mouse model which lacks an enzyme known as “PKC d ”, we have shown that this enzyme is essential for apoptosis in the mammary gland. We hypothesize that PKC d functions as a tumor suppressor and that loss of PKC d will increase mammary gland tumorigenesis. SPECIFIC AIMS AND STUDY DESIGN: In AIM 1 we will use the HER2/c-neu mouse model of human breast cancer to ask if loss of PKC d can accelerate tumor formation, progression or metastasis. This model is highly relevant to human breast cancer since amplification and/or overexpression of HER2/c-neu is seen in about 30% of tumors and correlates with a poor prognosis. We will ask if the frequency of mammary gland tumors and/or tumor metastasis is increased in the PKC d knock-out mice and in PKC d knock-out mice cross-bred with HER2/c-neu overexpressing mice. In AIM 2 we will explore the molecular mechanisms which underlie suppression of tumorigenesis by PKC d . Potential Outcome and Benefits of Research: Understanding how apoptosis is regulated is an intense area of interest since drugs which target these pathways are likely to be clinically very important. Conceivably, pro-apoptotic drugs could be designed to induce apoptosis directly, or to increase the responsiveness of the apoptotic machinery to conventional therapeutic drugs. Our studies will also enable the development of future models to determine if mammary specific overexpression of PKC d , or expression of an activated form of PKC d , can suppress tumor formation and/or metastasis, or increase chemo-sensitivity.