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Lorella Bonaccorsi, Daniele Nosi, Monica Muratori, Lucia Formigli, Gianni Forti and Elisabetta Baldi

different tumours, including prostate cancer (PC; Russell et al. 1998 ) where both EGF and EGFR are often up-regulated in particular in advanced stages ( Di Lorenzo et al. 2002 ). In addition to proliferation, EGFR plays a key role in invasion of cancer

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Prasenjit Dey, Rodrigo P A Barros, Margaret Warner, Anders Ström and Jan-Åke Gustafsson

Introduction In addition to their well-known role in growth and differentiation of the breast, ovary and uterus in females, and testes and prostate in males, estrogen is also required for proper functioning of the cardiovascular, immune

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Eiji Munetsuna, Sachie Nakabayashi, Rie Kawanami, Kaori Yasuda, Miho Ohta, Midori A Arai, Atsushi Kittaka, Tai C Chen, Masaki Kamakura, Shinichi Ikushiro and Toshiyuki Sakaki

of 25-hydroxyvitamin D 3 (25(OH)D 3 ) and its analogs ( Chen et al . 2000 , Dusso et al . 2005 ). Hence, 25(OH)D 3 and its analogs are considered to be pro-bioactive substances. Indeed, LNCaP, a human prostate cancer cell line, whose

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J Kim, L Jia, M R Stallcup and G A Coetzee

Introduction Untreated prostate cancer progresses from androgen-dependent tumors that respond favorably to clinical therapies to recurrent, metastatic, androgen-independent tumors that are invariably fatal. Even at the latter

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J Beilin, EM Ball, JM Favaloro and JD Zajac

The action of androgens is essential for the development of benign prostatic hyperplasia and carcinoma of the prostate. The androgen receptor is a ligand-dependent nuclear transcription factor. The transcriptional activation domain of the androgen receptor gene contains a polymorphic CAG repeat sequence. A shorter CAG repeat sequence within the normal range has been reported to be associated with increased risk of prostate cancer and symptomatic benign prostatic hyperplasia. Here, we examine the in vitro transcriptional activity of the androgen receptor (AR) with different numbers of CAG repeats within the normal range in a number of different cell lines of prostatic (LNCaP, PC3) and non-prostatic (COS-1, MCF7) origin. We utilize a luciferase reporter driven by the rat probasin promoter (-286/+28) containing two androgen receptor binding sites. Transcriptional activation of the androgen responsive reporter was observed to be greater with the AR containing 15 vs 31 CAG repeats in COS-1 cells (123.2+/-16.6 vs 78.2+/-10.9, P value 0.01) and the well differentiated prostate cancer cell line LNCaP (103.4+/-17.7 vs 81.4+/-7.7, P value 0.045). No difference was observed in the poorly differentiated prostate cancer cell line, PC3 (106.9+/-21.9 vs 109. 6+/-21.4, P>0.5) or the breast cancer cell line MCF7 (120.4+/-39.4 vs 103.1+/-23.1, P value >0.5). Dose-response experiments with varying quantities of ligand (0.01, 0.1, 1 and 10 nM dihydrotestosterone) or AR cDNA did not demonstrate significant differences in transactivation of the androgen responsive reporter in PC3 cells by the different AR constructs. This suggests that the lack of influence of CAG number in this prostatic cell line is not related to dose of ligand or quantity of androgen receptor. Western immunoblot analysis of androgen receptor protein in transiently transfected COS-1 cells did not demonstrate a difference in the expression of the androgen receptor protein with different numbers of CAG repeats following incubation in the presence or absence of androgen. Gel shift assay did not demonstrate increased DNA binding by androgen receptor with a shorter CAG repeat sequence. These experiments using a relatively androgen- and prostate-specific reporter provide evidence for an inverse relationship between androgen receptor transcriptional activity and the number of CAG repeats in the transcriptional activation domain. The effect of CAG repeat number was cell specific suggesting the involvement of accessory factors expressed differentially between different cell lines.

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HT Huynh, L Alpert, DW Laird, G Batist, L Chalifour and MA Alaoui-Jamali

Androgens play an important role in prostate gland development and function, and have been implicated in prostate carcinogenesis. We report the regulation of the gap junctional intercellular communication gene connexin 43 (Cx43) by androgens in the prostate gland. In rat ventral prostate tissue, only trace levels of Cx43 mRNA were detected. Castration, however, resulted in a high increase in Cx43 mRNA and protein. Cx32 was unchanged. Castration-induced Cx43 mRNA and protein were abolished by administration of dihydrotestosterone (DHT). Following castration, prostate weights were approximately 16% of sham-treated controls. However, DHT replacement resulted in prostate weights which were not different from sham-treated controls. Under similar castration conditions, Cx43 induction coincided with pronounced apoptosis in the prostate gland cells, and DHT prevented the induction of apoptosis. Given the physiological role of gap junctions and androgens in the regulation of prostate tissue homeostasis, our observations are relevant to the understanding of androgen-dependent prostate carcinogenesis.

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Michael Eisold, Mohammad Asim, Hanna Eskelinen, Thomas Linke and Aria Baniahmad

Introduction Prostate cancer (PCa) is the most often diagnosed cancer in males and the second cause of male cancer death in western countries ( Jemal et al . 2008 ). The growth of the normal prostate as well as of PCa is regulated by androgens

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Lai Jin, Chuanhua Li, Rong Li, Zongxing Sun, Xianjun Fang and Shengnan Li

−/−), had higher proliferation and migration rates compared with WT (CRH+/+) cells. In the prostate, cellular growth and differentiation are precisely regulated by autocrine and paracrine regulatory factors ( Cunha et al . 1987 ). Ectopic CRH, an endocrine

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M Maggiolini, AG Recchia, A Carpino, A Vivacqua, G Fasanella, V Rago, V Pezzi, PA Briand, D Picard and S Ando

The role of oestrogens in the development of prostate cancer is poorly understood. However, a large body of evidence has suggested that oestrogenic hormones may be involved in prostatic malignancy. The localization of oestrogen receptor beta (ERbeta) in the secretory epithelium of the human prostate has raised the intriguing possibility that the action of oestrogen could be mediated, at least in part, by this receptor during the process of carcinogenesis. Hence, specific interference with oestrogen-activated and ERbeta-mediated transcriptional activity could open new issues in the endocrine manipulation of prostate tumours. In the present study, we provide new insights into the role of ERbeta in the context of an androgen-responsive prostate cancer cell line such as LNCaP, which was used as a model system together with steroid receptor negative HeLa cells. ERbeta and the mutated androgen receptor (AR) T877A did not discriminate between oestrogen- or androgen-induced transactivation, whereas ERbeta and AR transcriptional activity were inhibited only by the respective hormone antagonists ICI 182,780 and casodex. Furthermore, the nuclear localization of ERbeta evaluated by immunocytochemistry confirmed the promiscuous response to hormones in addition to the specific inhibitory action of antagonists. Interestingly, ICI 182,780 and an ERbeta antisense expression vector repressed the growth effects of both 17beta-oestradiol and 5alpha-dihydrotestosterone, suggesting that ERbeta has a key role in the proliferation induced by these steroids in LNCaP prostate cancer cells. Thus our findings implicate ERbeta as a potential target for the treatment of prostate tumours.

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T Lyons-Darden and Y Daaka

Elevated levels of IGF-I in the circulation are associated with increased risk for the development of prostate cancer in men, and transgenic expression of human IGF-I in mouse epithelial prostate cells results in spontaneous prostate tumorigenesis. Little, however, is known about the mechanisms involved in the IGF-I-regulated growth of prostate cells. Here, we have demonstrated that treatment with IGF-I induces the activation of the mitogenic extracellular signal-regulated kinase (ERK) pathway and the growth of human prostate cells. Stimulation with IGF-I also promoted the tyrosine phosphorylation of epidermal growth factor receptor (EGFR). Signal relay from IGF-I to ERK requires heterotrimeric G proteins and EGFR; inhibition of Gi/o protein activation by pertussis toxin, or EGFR by tyrphostin AG1478 obliterated the ability of IGF-I to promote ERK activation. Further, treatment with pertussis toxin inhibited the IGF-I-mediated prostate cell growth. These data demonstrated the requirement of heterotrimeric G proteins in IGF-I-regulated prostate cell growth and suggest the potential utility of the G proteins as effective drug targets to combat this common cancer.