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    Awarded Grants
    Mechanism of Protein Kinase C Alpha-Mediated Tamoxifen-Resistant Breast Cancer

    Scientific Abstract:
    Resistance to tamoxifen (TAM), currently the most often prescribed endocrine treatment for breast cancer, represents a significant problem in the management of the disease. Identification of the key factors involved in the molecular mechanism of TAM resistance will likely lead to the development of logical therapeutic modalities. We have demonstrated that overexpression of protein kinase C alpha (PKCá) into the hormone-dependent T47D:A18 breast cancer cell line results in a hormone-independent phenotype in vitro. Tumors derived from these cells grow in ovariectomized athymic mice in the absence of hormonal stimulation and despite TAM administration. Most interesting is our finding that these tumors regress in the presence of 17â-estradiol (E2). This may have important implications for the treatment of breast cancer since we have reported that overexpression of PKCá may be a marker for TAM-resistance in patients. Tumors overexpressing PKCá may not be growth-inhibited if the patient is given TAM, and a more appropriate therapy may be an estrogen-like compound. This therapeutic approach was considered standard therapy prior to the introduction of TAM into the clinic. Treatment of patients with diethylstilbestrol (DES) was shown to have a survival advantage compared with TAM, although TAM was better tolerated. It is our hypothesis that perhaps pre-selection of a subset of patients that overexpress PKCá may greatly improve upon the therapeutic response with DES. However, before this information can be translated into the clinic, it is imperative that mechanistic information be obtained. The overall goal of this study is to identify the signaling pathway(s) that play a role in E2-induced regression in a PKCá-overexpressing human tumor model. To achieve this goal, we will address the following specific aims: 1. Identify the cell:extracellular matrix interaction required to elicit E2-induced tumor regression; 2. Determine the signaling events leading to apoptosis; 3. Determine the role of the estrogen receptors, ERá and ERâ, in E2-induced tumor regression. Achievement of these aims will pave the way to pursuing pre-clinical studies to address possible therapeutic options for the treatment of TAM-resistant breast cancer.

    Lay Abstract:
    Tamoxifen is a hormonal therapy that is used to treat approximately two-thirds of patients with breast cancer. Estrogen stimulates the growth of breast tumors because the tumors express the estrogen receptor. Tamoxifen blocks the ability of estrogen to activate the estrogen receptor. Unfortunately, resistance to tamoxifen occurs in most cases of advanced cancer, and many tumors are resistant to the therapy at the outset. Understanding the mechanism of tamoxifen-resistance will help to devise alternative treatment approaches. Our laboratory has determined that elevated expression of a key cell signaling enzyme, protein kinase C alpha (PKCa), can cause tamoxifen resistance in a breast cancer cell line. We have developed human breast tumors in mice that produce high levels of PKCa and have determined that these tumors are not only resistant to tamoxifen, but they can be completely eliminated by administration of estradiol, a phenomenon that has been described, but as of yet been explained. Furthermore, patients that have high expression of PKCa suffer cancer recurrence following tamoxifen therapy at a much higher frequency that those patients that remain free of their cancer. We will elucidate the mechanism of PKCa-mediated tamoxifen resistant breast cancer to identify novel therapeutic approaches and determine better management strategies for patients that exhibit elevated PKCa expression.