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Lynn Birch

Publications and source records attributed to Lynn Birch.

7 recordsLinked to original sources
PubMed2007

Androgen regulation of prostate morphoregulatory gene expression: Fgf10-dependent and -independent pathways.

Androgens are essential and sufficient for prostate gland morphogenesis; however, the downstream gene targets that mediate this action are unclear. To identify androgen-regulated genes involved in prostate development, we used short-term organ culture and examined the effect of testosterone on the expression of several critical prostate morphoregulatory genes. Rat ventral prostates (VP) and lateral prostates (LP) were collected at birth, and contralateral lobes were cultured for 18 h in the presence or absence of 10 nM testosterone with or without OH-flutamide to block residual androgens. Gene expression was quantitated using real-time RT-PCR. Although expression of Fgf10, Nkx3.1, and Ptc was increased in both prostate lobes, other genes were regulated by testosterone in a lobe-specific manner. This included up-regulation of epithelial genes FgfR2iiib, Shh, Hoxb13, and Bmp7 in the VP specifically and down-regulation of mesenchymal genes Wnt5a (VP) and Bmp4 (LP). Thus, in addition to stimulation of homeobox genes and paracrine-acting growth factors, androgens may positively regulate prostatic development through suppression of growth inhibitory genes. Because previous studies revealed a similar gene regulation pattern in response to exogenous Fgf10, experiments were performed to identify androgen-regulated genes mediated through Fgf10 signaling. Short-term VP and LP cultures with FgfR antagonist PD173074 and Mek inhibitor U0126 identified epithelial Shh and Hoxb13 up-regulation by androgens to be Fgf10-dependent. We propose that androgen regulation of prostate development is mediated through positive and negative regulation of multiple morphoregulatory genes acting in combination through complex gene networks. Lobe-specific responses may provide a developmental basis for prostate gland heterogeneity.

Animals↗
PubMed2006

Developmental estrogen exposures predispose to prostate carcinogenesis with aging.

Prostate morphogenesis occurs in utero in humans and during the perinatal period in rodents. While largely driven by androgens, there is compelling evidence for a permanent influence of estrogens on prostatic development. If estrogenic exposures are abnormally high during the critical developmental period, permanent alterations in prostate morphology and function are observed, a process referred to as developmental estrogenization. Using the neonatal rodent as an animal model, it has been shown that early exposure to high doses of estradiol results in an increased incidence of prostatic lesions with aging which include hyperplasia, inflammatory cell infiltration and prostatic intraepithelial neoplasia or PIN, believed to be the precursor lesion for prostatic adenocarcinoma. The present review summarizes research performed in our laboratory to characterize developmental estrogenization and identify the molecular pathways involved in mediating this response. Furthermore, recent studies performed with low-dose estradiol exposures during development as well as exposures to environmentally relevant doses of the endocrine disruptor bisphenol A show increased susceptibility to PIN lesions with aging following additional adult exposure to estradiol. Gene methylation analysis revealed a potential epigenetic basis for the estrogen imprinting of the prostate gland. Taken together, our results suggest that a full range of estrogenic exposures during the postnatal critical period - from environmentally relevant bisphenol A exposure to low-dose and pharmacologic estradiol exposures - results in an increased incidence and susceptibility to neoplastic transformation of the prostate gland in the aging male which may provide a fetal basis for this adult disease.

Aging↗
PubMed2006

MHC class I and class II molecules are expressed in both human and mouse prostate tumor microenvironment.

BACKGROUND: There has been a determined search for therapies specifically aimed at eradicating tumor cells while leaving normal host cells unaffected. This goal can potentially be accomplished by engaging tumor antigen-specific T-cell repertoire to attack the tumor. A pre-requisite for a successful T-cell-mediated attack against tumors or pathogens is that the target tissues express major histocompatibility complex (MHC) molecules. Using newer anti-MHC class I and MHC class II antibody reagents, we re-examined the expression of MHC in both human and mouse prostate tumors and their microenvironments. METHODS: Using immunocytochemistry, we examined the expression of MHC class I, class II, and CD3 molecules on cryopreserved human and mouse prostate tumor samples. RESULTS: MHC class I molecules are expressed by the entire spectrum of different stages of both human and mouse prostate tumor cells. Additionally, cells of the hematopoietic lineage, dispersed in the tumor microenvironment, showed significant expression of MHC class II molecules. Human prostate tumors also show a significant infiltrate of CD3+ T cells. CONCLUSIONS: Expression of MHC class I and class II molecules within the prostate tumor microenvironment are consequential for T-cell-mediated immunotherapeutic approaches against prostate cancer.

Aged↗
PubMed2005

The role of Fgf10 signaling in branching morphogenesis and gene expression of the rat prostate gland: lobe-specific suppression by neonatal estrogens.

Brief exposure of rats to high-dose estrogen during the neonatal period interrupts prostate development in a lobe-specific manner and predisposes the gland to dysplasia with aging, a phenomenon referred to as developmental estrogenization. Our previous studies have revealed that these effects are initiated through altered steroid receptor expression; however, the immediate downstream targets remain unclear. We have recently shown that developmental expression of Shh-ptc-gli is downregulated in the dorsolateral prostate following estrogenization, and this is responsible, in part, for branching deficits observed in that prostatic region specifically. In the present study, we examine the role of Fgf10 signaling during rat prostate development and as a mediator of the developmental estrogenized phenotype. Fgf10 and FgfR2iiib localize to the distal signaling center of elongating and branching ducts in separate prostate lobes where they regulate the expression of multiple morphoregulatory genes including Shh, ptc, Bmp7, Bmp4, Hoxb13, and Nkx3.1. Ventral and lateral lobe organ cultures and mesenchyme-free ductal cultures demonstrate a direct role for Fgf10/FgfR2iiib in ductal elongation, branching, epithelial proliferation, and differentiation. Based on these findings, a model is proposed depicting the localized expression and feedback loops between several morphoregulatory factors in the developing prostate that contribute to tightly regulated branching morphogenesis. Similar to Shh-ptc-gli, neonatal estrogen exposure downregulates Fgf10, FgfR2iiib, and Bmp7 expression in the dorsolateral prostate while ventral lobe expression of these genes is unaffected. Lateral prostate organ culture experiments demonstrate that growth and branching inhibition as well as Fgf10/FgfR2iiib suppression are mediated directly at the prostatic level. Furthermore, exogenous Fgf10 fully rescues the growth and branching deficits due to estrogen exposure. Together, these studies demonstrate that alterations in Fgf10 signaling are a proximate cause of Shh-ptc-gli and Bmp7 downregulation that together result in branching inhibition of the dorsolateral prostate following neonatal estrogen exposure.

Aging↗
PubMed2003

Neonatal estrogen down-regulates prostatic androgen receptor through a proteosome-mediated protein degradation pathway.

Brief exposure of male rats to estrogens during the neonatal period interrupts normal prostate development, alters epithelial cell differentiation, and predisposes this gland to hyperplasia and severe dysplasia analogous to prostatic intraepithelial neoplasia (PIN) with aging. Previous work demonstrated that the reduced growth, secretory activity, and androgen sensitivity that are observed in the adult ventral lobe are a function of reduced androgen receptor (AR) levels. Down-regulation of AR protein was found to occur immediately following neonatal exposure to estradiol benzoate (EB) and persist through adulthood and aging, indicating a permanent imprint on the ability of the prostate to express normal AR levels. To determine the intracellular mechanism of AR down-regulation by estrogens, the present study examined the effect of neonatal EB on AR gene transcription, mRNA levels, protein translation, and protein degradation in the d 10 ventral prostate glands. Nuclear run-on assays showed no alteration in AR gene transcription following exposure to EB on d 1-5 compared with controls. In situ hybridization and quantitative (q) RT-PCR revealed no difference in mRNA levels in the stromal or epithelial cells in response to estrogen exposure which, taken together, indicate that estrogen down-regulation of AR is mediated at the posttranscriptional level. AR translation was assessed with an in vitro transcription-translation assay in the presence of prostatic lysates from oil and estrogen-exposed animals, and no treatment effect was noted. AR degradation was examined in an in vitro assay validated with adult intact and castrate prostates. Prostatic lysates from intact rats initiated AR degradation with a t1/2 of 2.31 h, whereas proteins from castrate rats accelerated AR degradation to a t1/2 of 1.34 h (P < 0.001). Prostatic lysates from control d 10 prostates induced AR degradation with a t1/2 of 1.49 h, whereas estrogenized prostates increased AR degradation to a t1/2 of 1.11 h (P < 0.001). Proteosome inhibitors MG132 and ALLnL were able to reverse AR degradation induced by prostatic lysates from adult intact and castrate rats as well as from developing and estrogenized prostates, indicating that AR degradation was mediated through the proteosome pathway. Furthermore, the proteosome-mediated AR degradation in the estrogenized d 10 prostate was associated with a marked suppression of Akt phosphorylation that has been linked to AR degradation in other systems. Taken together, the present data show that exposure to neonatal estrogens down-regulates AR protein levels in the ventral prostate gland by accelerating AR degradation, which is mediated through the proteosome pathway.

Animals↗
PubMed2003

The role of prolactin in the prostatic inflammatory response to neonatal estrogen.

Estrogen exposure in the neonatal rat has been shown to disrupt the normal morphology and development of the prostate gland. The response to this exposure is manifest in adulthood as epithelial dysplasia and chronic inflammation. This inflammatory response consists of infiltrating T-lymphocytes and macrophages, which is typically observed in chronic prostatitis in both rodents and humans. In our rat model, the developmental hormonal milieu is altered following estrogenization, resulting in transient hyperprolactinemia, which begins prepubertally (postnatal d 21) and persists throughout puberty. The purpose of this experiment was to determine the role of prolactin (PRL) in the altered phenotype of the adult rat prostate exposed to neonatal estrogen. Male Sprague Dawley rat pups (n = 104) were randomized at birth to receive oil or estradiol benzoate on postnatal d 1, 3, and 5. They were further randomized to receive bromocriptine (BrC) pellets or placebo at d 15. Animals were killed at d 90. Serum PRL and testosterone levels, prostate lobe, and hormone-dependent and immune-related tissue weights and histology were examined. Animals receiving BrC had significantly lower PRL levels at d 90, regardless of estrogen status. Prostate lobe and testicular weights were significantly reduced in estrogenized animals vs. controls, and BrC did not abate this response, indicating that growth inhibition is not mediated through hyperprolactinemia. Splenic and thymus weights were greater in estrogenized animals, and this was partially reversed with BrC. Neonatal estrogen exposure resulted in a marked infiltration of CD4+ and CD8a+ lymphocytes in the prostate gland, and this was partially reversed by concomitant BrC treatment. In contrast, the estrogen-induced macrophage infiltration of the prostate was not affected by PRL suppression. These findings indicate that prostatic inflammation and immune cell infiltration in the prostate gland of neonatally estrogenized rats is mediated through a PRL-dependent as well as a PRL-independent mechanism. As prostatic inflammation or prostatitis in humans is associated with benign prostatic hyperplasia and prostatic carcinoma, this animal model may provide mechanistic insight with regards to age-associated prostatic lesions.

Animals↗