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Freddie Pruitt, Ph.D.

Department: Cancer Biology, 2013

Faculty Mentor: Simon Hayward, Ph.D.

Dissertation Title: A role for estrogen receptor and the estrogen-regulated protease cathepsin D in stromally-driven prostatic carcinogenesis

Dissertation AbstractStromal-epithelial interactions are important in both prostate development and cancer. Stromal changes have been shown to be powerful prognostic indicators of prostate cancer progression and of patient death helping to define lethal versus indolent phenotypes. The specific molecular underpinnings of these interactions are incompletely understood. Several molecules found to be aberrantly expressed in cancer associated fibroblasts (CAFs) (including cyclin D1 [CD1], stromal derived factor 1 [SDF-1]) contribute to tumorigenesis and malignant transformation in xenograft experiments. These molecules can be regulated by a number of different factors, but are both putative estrogen regulated genes. In this study, we show that dysregulation of ERα expression in cancer associated stroma results in the differential regulation of estrogen responsive genes that are key factors in enhancing the invasive potential of the epithelial tumor. The cell cycle regulator CD1 and the estrogen receptor are known to interact and can induce estrogenic gene transcription. Cathepsin D (CathD) is an estrogen regulated aspartic endopeptidase, known to be involved in a number of physiological processes as well as in the regulation of apoptosis. In this study, we highlight CathD as a mediator of cancer associated stromal promotion of prostate tumorigenesis. An examination of human prostate tissue revealed significantly increased stromal staining of CathD in malignant prostate tissue in comparison to benign prostate tissue. Stromal specific overexpression of CathD in benign prostate stromal cells induced malignancy in adjacent epithelium through increased TGFβ signaling and responsive gene expression. The proteolytic function of stromally-derived CathD is dependent on the activity of hydrogen-proton pump activity on the surface of prostate epithelial cell lines. The study presented here indicates that CathD is not only an important mediator of stroma-epithelial cross talk, but also an essential component in promotion of tumorigenesis in vivo, and Inhibition of ER signaling in the cancer associated stroma inhibits malignant transformation in the adjacent epithelium.