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Gail S. Prins' Research Interests
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Dr. Prins' research interests concern basic and applied studies in prostate gland growth and carcinogenesis. The primary research focus of my laboratory is the hormonal control of prostatic development, growth and function and how abnormalities in these systems contribute to aging-associated disease. Areas of emphasis include steroid receptor expression, developmental regulatory networks, developmental estrogenization, environmental estrogenic exposures, growth hormone and carcinogenesis, and the role of selenium and selenoproteins in prostate cancer prevention.
A major research effort, which has spanned two decades, is elucidation of the hormonal regulation of steroid receptor expression and the interrelationship between this regulation and the normal and pathological growth of the prostate gland. Although we have applied some of these findings to the human prostate, the majority of these studies have used the rodent as an animal model for tissue heterogeneity and disease. Our work has described the ontogeny and adult expression patterns of prostatic androgen receptor, estrogen receptors (α and β), progesterone receptor, retinoic acid receptors (RAR and RXR α,β,γ) as well as retinoid metabolizing enzymes and binding proteins and have found that each of these receptors has distinct localization in specific cell types which change over the course of development in the three prostate lobes. Importantly, they are differentially regulated by hormones (androgens, estrogens, prolactin) which leads to complexity in response to the hormonal milieu. Recent studies on regulatory mechanisms have determined that autoregulation of the androgen receptor as well as its down-regulation by estrogens is mediated at the posttranscriptional level through targeted proteolysis via ubiquitination and proteosome-mediated protein degradation.
Another major research interest concerns the effects of early developmental exposures to estrogens on the prostate gland, a phenomenon referred to as estrogen imprinting or Developmental Estrogenization. The rat and mouse prostate undergo morphogenesis after birth and this process can be imprinted by brief exposure to endogenous and exogenous hormones. We have demonstrated that neonatal estrogen exposure permanently imprints prostatic development and is associated with an increased incidence of hyperplasia, dysplasia and adenocarcinoma with aging. Thus, neonatal estrogenization of the rat has evolved as a useful model to evaluate the role of exogenous and endogenous estrogens as a predisposing factor for prostatic diseases later in life. The current objective of our research is to elucidate the cellular and molecular mechanisms by which neonatal estrogens initially imprint or transform the prostate gland. Towards this end, our recent studies with ERα knockout mice and βERKO mice demonstrated that effects of estrogens are initially mediated through ERα which is amplified within prostatic stromal cells. We further determined that key members of the steroid receptor superfamily - AR, ERα, ERβ, PR and RAR α and β - which are expressed in a temporal and cell-specific manner during prostate development are drastically altered by early estrogenic exposure as shown in the diagram below. This effectively shifts the developing prostate from an androgen-regulated gland to one driven by estrogens and retinoids (shown on schematic below).
The net result is that programming and organizational signals which normally dictate and determine prostate development during discrete temporal windows are permanently and irretrievably altered.
Ongoing studies in our laboratory are focused on identifying the developmental genes downstream of androgen and estrogen in the developing prostate. Following estrogenic exposures during development, we have demonstrated decreased expression of the epithelial homeobox genes Hoxb-13 and Nkx3.1, which are critical for normal epithelial cell differentiation which, in part, explains the epithelial differentiation defects observed as the animal ages. In addition, paracrine signaling pathways show lobe-specific responses to estrogenic exposures which result in branching defects in the dorsolateral prostate lobes. Specific pathways delineated to date include sonic hedgehog-patched-gli, Fgf10/FgfR2iiib and Bmp4/Bmp7/Smad and the current data suggest that the estrogenization is initiated through alterations in Fgf10 signaling which results in a cascade of alterations in critical developmental genes. In summary, these alterations in morphoregulatory gene expression lead to growth retardation, differentiation aberrations and predisposure to adult-onset PIN as summarized in the schematic at right.
Two related projects in our laboratory on the developmental estrogenization pathway concentrate on 1) gene methylation patterns that are imprinted by early exposures to both natural and environmental that may help to explain the molecular basis for permanent alterations in gene expression, and 2) oxidative stress pathways that are initiated in response to estrogenic imprints which in turn lead to prostatic dysplasia with aging.
This work serves as a model for what might be expected to occur in the prostate gland's of sons of DES-exposed mothers as well as toxicologic exposure to environmental and dietary estrogens which is a major problem now confronting the scientific and medical community.
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