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    Research Grants Awarded

    Function And Mechanism(S) For E-Cadherin Loss In Breast Cancer

    Grant Mechanism:
    Career Catalyst Research

    Scientific Abstract:
    Considerable evidence has accumulated that mammary tumors expressing reduced levels of E-cadherin, a cell-cell adhesive protein which prevents epithelial cancers from forming, is associated with a higher 5-year all-cause mortality risk. In addition, a plethora of in vitro and clinical data supports a tumor suppressive role for E-cadherin in the development of all breast cancers. Other studies show a pivotal role for cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) synthesis in this process. More specifically, epidemiology studies over the past two decades have demonstrated that intake of non-steroidal anti-inflammatory drugs (NSAIDs), which exerts its anti-tumorigenic activity by suppression of cyclooxygenase and PGE2 production, significantly reduces the rate of developing breast cancers. Moreover, PGE2 produced by tumor cells or tumor-associated host cells have long been considered to play a stimulatory role in tumor progression and metastases. However, despite these independent reports demonstrating loss of E-cadherin and enhanced COX-2-drived PGE2 in mammary tumors, there has been no direct evidence showing a link between PGE2 and E-cadherin down-regulation. Moreover, the biochemical and cellular pathways through which this COX-2-induced PGE2 signaling regulates E-cadherin processing and down-regulation, has yet to be elucidated. We have previously demonstrated that addition of PGE2 or the prostaglandin E2 EP2 receptor agonist, Butaprost, to epithelial cells produces a dose- and time-dependent decrease in E-cadherin. Similarily, our preliminary data using the well-differentiated human breast cancer epithelial cell line MCF7, demonstrates internalization and loss of E-cadherin staining after exogenous addition of PGE2 or the EP2 agonist Butaprost. Both pharmacologic agents also induced dramatic alterations in the morphology of these cells. Furthermore, we have previously shown that the PGE2-EP2 signaling pathway may initiate tumorigenesis in epithelial cells by down-regulating E-cadherin mediated cell-cell contacts via its mobilization away from the cell membrane, internalization into the cytoplasm and its shuttling through the lysosome and proteasome degradation pathways. Therefore, based on our previous reports and preliminary data we hypothesize that E-cadherin down-regulation in breast cancers is a post-translational event regulated by the PGE2/EP2 signaling pathway. To this end, E-cadherin loss in epithelial tissues appears to be mediated by persistent activation of internalization and degradation, ultimately contributing to carcinogenic progression. Therefore, in this proposal we will use gain and loss-of-function approaches in mice to evaluate the role of E-cadherin in the development and progression of breast cancers in vivo. Lastly, we will determine the mechanism(s) by which PGE2-EP2 signaling regulates E-cadherin down-regulation. New insights on how specific degradative/proteolytic pathways contribute to E-cadherin downregulation will provide new therapeutic targets for breast cancer. Finally, the discovery of the aforementioned ?crosstalk? between the PGE2/EP2 signaling pathway and post-translational E-cadherin regulation may lead to the development of novel prognostic markers and avenues for breast cancer therapy.

    Lay Abstract:
    Breast cancer is one of the most common types of cancer among women in the United States, with 213,000 new cases and 41,000 deaths anticipated for 2006. Five-year survival following breast cancer diagnosis is dependent upon a spectrum of biologic factors including age, menopausal status, tumor stage, grade and hormone receptor status, as well as race and socioeconomic status. However, although there have been dramatic breakthroughs in mammographic detection of breast tumors, the cellular and molecular pathways involved in these cancers, has yet to be elucidated. We hypothesize that loss of E-cadherin expression in mammary epithelial cells is critical in the initiation, progression and development of mammary cancers. This protein has been shown to inhibit breast cancers, by maintaining cell-cell adhesive contacts, thereby inhibiting tumor cell proliferation, migration and invasion. We further propose that prostaglandin E2 (PGE2, the cellular product of cyclooxygenase-2 whose formation induces breast cancers), via its downstream EP2 receptor, imparts this pro-oncogenic loss of E-cadherin by re-routing/processing this glycoprotein toward distinct proteolytic pathways for degradation. Therefore, our proposed studies will first determine whether loss of E-cadherin is necessary and sufficient in the development of breast cancers using the well established 9,10-dimethyl-1,2-benzanthracene (DMBA) mammary carcinogenesis model. DMBA-induced mammary gland tumors in rodents, has been widely used as a preclinical animal model for the development of chemopreventive drugs for breast cancers in patients. Next we will evaluate the expression of E-cadherin and the development of breast cancers in EP2 receptor knock-out (lack the EP2 receptor) and knock-in (overexpress the EP2 receptor) mice after exposure to DMBA. Lastly, we will investigate whether EP2 receptor signaling induces E-cadherin down-regulation via post-translational modifications in vitro, including E-cadherin internalization and proteolytic degradation in the lysosome and proteosome. We will also assess whether PGE2-EP2-mediated ubiquitin tagging of E-cadherin is involved in these aforementioned processes. Our studies represent an integrated investigation that will, with future E-cadherin knock-in strategies, definitively test whether E-cadherin loss is critical in the development and progression of mammary cancers. Moreover, we will extend our knowledge on the role of PGE2-EP2 signaling on E-cadherin down-regulation in breast carcinogenesis in mice. Our studies will also provide new insights on how these PGE2-EP2-mediated degradative pathways contribute to E-cadherin loss in cultured cells. This newly described link between enhanced PGE2-EP2 signaling and E-cadherin down-regulation will provide new targets for anti-invasive therapy. In addition, the discovery of ?crosstalk? between the PGE2/EP2 signaling pathway and post-translational E-cadherin regulation may lead to the development of novel prognostic markers and avenues for cancer therapy. In the future, these strategies may be used in the clinical setting to facilitate early diagnosis and increase survivability rates for these patients. Finally, the proposed Career Development Plan will ensure the candidate has the necessary training to take this proposal from the bench to the bedside. That is, the Komen Career Catalyst Grant will train the candidate to identify novel scientific discoveries and their potential clinical usefulness in animal models (preclinical studies) in the laboratory, (2) evaluate such discoveries through clinical trials and (3) bring their use to clinical practice (bench?to?bedside?to?curb).