Tumor Suppression by Protein Kinase C-delta

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DESCRIPTION (provided by applicant): Protein kinase C delta (PKC d) negatively regulates cell cycle progression and has been proposed to be a tumor suppresser gene. Consistent with this hypothesis, the PKC d gene localizes to a region on chromosome 3p where several tumor suppresser genes are thought to reside. While a role for PKC d as a negative regulator of proliferation has been established, little is known as to how PKC d exerts this effect, nor whether PKC d function is suppressed or lost in human cancer. The major objective for this proposal is to determine how PKC d impacts upon cell proliferation and survival in human breast cancer cells. Preliminary studies with breast cancer cell lines indicate non-random differences in the level of PKC d expression in different breast cancer cell lines with different cancerous phenotypes. We propose that tumor-suppressing effects of PKC d can be exploited to negatively regulate cell proliferation and induce apoptosis in human breast cancer cells. Specifically, we propose to: Aim 1: To characterize PKC d expression in breast cancer cell lines with different genetic defects. We will determine whether expression of PKC d correlates with specific genetic alterations such as p53 status, loss of estrogen receptor, or tyrosine kinase expression. Aim 2: To characterize the impact of PKC d activity upon cell cycle progression and apoptosis in breast cancer cells. Aim 3: To determine whether p53 expression can be enhanced by elevated expression of PKC d or by PKC d agonists such as bryostatin1 and bistratene A. Aim 4: To characterize the role that PKC d plays in suppressing metastatic phenotypes. We will examine the effect of PKC d upon cell migration, invasion and protease secretion. The studies proposed here will characterize a potentially important indicator of tumor status--that being the expression of PKC d in breast cancer cells with different genetic backgrounds. Based on preliminary studies that have revealed a PKC d requirement for p53 expression, it is proposed that inhibiting PKC d would have tumor-promoting effects by preventing the expression of p53. And more importantly, activating PKC d with compounds like bryostatin1 could have tumor suppressing effects that could be exploited therapeutically.