Steroid hormones and carcinogenesis of the prostate: the role of estrogens

doi:10.1111/j.1432-0436.2007.00224.x

Differentiation

Volume 75, Issue 9, November 2007, Pages 871-882

https://doi.org/10.1111/j.1432-0436.2007.00224.x Get rights and content

Abstract

Androgens have long been known to be the major sex hormones that target the prostate during development, maturation, and carcinogenesis. It is now apparent that estrogens, both those synthesized by the body as well as those from our environment, also target the prostate during all stages of development. Little is known about the mechanisms involved in estrogen stimulation of carcinogenesis and less is known about how to prevent or treat prostate cancer through estrogenic pathways. To better understand how estrogens mediate their carcinogenic effects, the respective roles of estrogen receptor (ER)-α and ER-β must be elucidated in the epithelial and stromal cells that constitute the prostate. Lastly, the significance of ER signaling during various ontogenic periods must be determined. Answers to these questions will further our understanding of the mechanisms of estrogen/ER signaling and will serve as a basis for chemopreventive and/or chemotherapeutic strategies for prostate cancer.

References (130)

Y. Arai et al.
Long-term effects of perinatal exposure to sex steroids and diethylstilbestrol on the reproductive system of male mammals
Int Rev Cytol
(1983)
H. Bonkhoff et al.
Estrogen receptor expression in prostate cancer and premalignant prostatic lesions
Am J Pathol
(1999)
J.F. Couse et al.
Estrogen receptor-alpha mediates the detrimental effects of neonatal diethylstilbestrol (DES) exposure in the murine reproductive tract
Toxicology
(2004)
G.R. Cunha et al.
Hormonal, cellular, and molecular regulation of normal and neoplastic prostatic development
J Steroid Biochem Mol Biol
(2004)
F.E. Domann et al.
Flipping the epigenetic switch
Am J Pathol
(2004)
J.K. Dow et al.
Fibroblast growth factor 2: its structure and property, paracrine function, tumor angiogenesis, and prostate-related mitogenic and oncogenic functions
Urology
(2000)
L. Ellis et al.
Racial/ethnic variations in male testosterone levels: a probable contributor to group differences in health
Steroids
(1992)
C. Gennigens et al.
Insulin-Like Growth Factor (IGF) family and prostate cancer
Crit Rev Oncol Hematol
(2006)
A. Gray et al.
An examination of research design effects on the association of testosterone and male aging: results of a meta-analysis
J Clin Epidemiol
(1991)
L. Kangas
Review of the pharmacological properties of toremifene
J Steroid Biochem
(1990)

I. Leav et al.

Comparative studies of the estrogen receptors beta and alpha and the androgen receptor in normal human prostate glands, dysplasia, and in primary and metastatic carcinoma

Am J Pathol

(2001)

Y. Li et al.

Gene expression profiles of genistein-treated PC3 prostate cancer cells

J Nutr

(2002)

S.I. Makela et al.

Dietary soybean may be antiestrogenic in male mice

J Nutr

(1995)

M.M. Montano et al.

Identification and characterization of a novel factor that regulates quinone reductase gene transcriptional activity

J Biol Chem

(2000)

G. Mor et al.

Regulation of fas ligand expression in breast cancer cells by estrogen: functional differences between estradiol and tamoxifen

J Steroid Biochem Mol Biol

(2000)

P. Ofner et al.

Differential effects of diethylstilbestrol and estradiol-17 beta in combination with testosterone on rat prostate lobes

Toxicol Appl Pharmacol

(1992)

G.S. Prins et al.

Image analysis of androgen receptor immunostaining in prostate cancer accurately predicts response to hormonal therapy

J Urol

(1998)

L. Pylkkanen et al.

Prostatic dysplasia associated with increased expression of c-myc in neonatally estrogenized mice

J Urol

(1993)

L.R. Qadan et al.

2-Methoxyestradiol induces G2/M arrest and apoptosis in prostate cancer

Biochem Biophys Res Commun

(2001)

ACS (2006) Cancer Facts & Figures, 2006, p....

A. Bardin et al.

Loss of ERbeta expression as a common step in estrogen-dependent tumor progression

Endocr Relat Cancer

(2004)

A. Belanger et al.

Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men

J Clin Endocrinol Metab

(1994)

R.C. Bergan et al.

A phase II study of high-dose tamoxifen in patients with hormone-refractory prostate cancer

Clin Cancer Res

(1999)

M.C. Bosland

The role of steroid hormones in prostate carcinogenesis

J Natl Cancer Inst Monogr

(2000)

M.C. Bosland et al.

Induction at high incidence of ductal prostate adenocarcinomas in NBL/Cr and Sprague-Dawley Hsd: SD rats treated with a combination of testosterone and estradiol-17 beta or diethylstilbestrol

Carcinogenesis

(1995)

C.B. Brendler et al.

Spontaneous benign prostatic hyperplasia in the beagle. Age-associated changes in serum hormone levels, and the morphology and secretory function of the canine prostate

J Clin Invest

(1983)

D.L. Buchanan et al.

Role of stromal and epithelial estrogen receptors in vaginal epithelial proliferation, stratification, and cornification

Endocrinology

(1998)

J.M. Chan et al.

Diet after diagnosis and the risk of prostate cancer progression, recurrence, and death (United States)

Cancer Causes Control

(2006)

W.Y. Chang et al.

Neonatal estrogen stimulates proliferation of periductal fibroblasts and alters the extracellular matrix composition in the rat prostate

Endocrinology

(1999)

T. Colborn et al.

Developmental effects of endocrine-disrupting chemicals in wildlife and humans

Environ Health Perspect

(1993)

J.F. Couse et al.

Estrogen receptor null mice: what have we learned and where will they lead us?

Endocr Rev

(1999)

G.R. Cunha et al.

Role of the stromal microenvironment in carcinogenesis of the prostate

Int J Cancer

(2003)

G.R. Cunha et al.

The importance of stroma in morphogenesis and functional activity of urogenital epithelium

In Vitro

(1979)

G.R. Cunha et al.

Estrogenic effects on prostatic differentiation and carcinogenesis

Reprod Fertil Dev

(2001)

B. Dahllof et al.

Estramustine depolymerizes microtubules by binding to tubulin

Cancer Res

(1993)

F.H. de Jong et al.

Peripheral hormone levels in controls and patients with prostatic cancer or benign prostatic hyperplasia: results from the Dutch–Japanese case-control study

Cancer Res

(1991)

J.P. Deslypere et al.

Influence of age on steroid concentrations in skin and striated muscle in women and in cardiac muscle and lung tissue in men

J Clin Endocrinol Metab

(1985)

D. Djakiew

Role of nerve growth factor-like protein in the paracrine regulation of prostate growth

J Androl

(1992)

J.R. Drago

The induction of NB rat prostatic carcinomas

Anticancer Res

(1984)

S. Dupont et al.

Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes

Development

(2000)

S.J. Ellem et al.

Aromatase and prostate cancer

Minerva Endocrinol

(2006)

S.J. Ellem et al.

Local aromatase expression in human prostate is altered in malignancy

J Clin Endocrinol Metab

(2004)

H.A. Feldman et al.

Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study

J Clin Endocrinol Metab

(2002)

T. Fixemer et al.

Differential expression of the estrogen receptor beta (ERbeta) in human prostate tissue, premalignant changes, and in primary, metastatic, and recurrent prostatic adenocarcinoma

Prostate

(2003)

A. Gray et al.

Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts male aging study

J Clin Endocrinol Metab

(1991)

K. Griffiths

Estrogens and prostatic disease. International Prostate Health Council Study Group

Prostate

(2000)

M. Hamilton et al.

A phase I/II study of high-dose tamoxifen in combination with vinblastine in patients with androgen-independent prostate cancer

Acta Oncol

(2003)

R.B. Hayes et al.

Physical characteristics and factors related to sexual development and behaviour and the risk for prostatic cancer

Eur J Cancer Prev

(1992)

B.E. Henderson et al.

The early in utero oestrogen and testosterone environment of blacks and whites: potential effects on male offspring

Br J Cancer

(1988)

S.M. Ho et al.

Estrogens and antiestrogens as etiological factors and therapeutics for prostate cancer

Ann N Y Acad Sci

(2006)

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Unlike androgens, estrogens work primarily through 2 cognate receptors, estrogen receptor α (ERα) and estrogen receptor β (ERβ). In the prostate, several lines of evidence support the concept that ERα promotes prostatic epithelial proliferation during carcinogenesis, whereas ERβ functions as a tumor suppressor [3,4,14,17]. Because ERβ is considered to be lost during PRCA progression [14,17], this study will focus on the role of ERα.
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The prostanoid thromboxane (TX) A₂ plays a central role in hemostasis and is increasingly implicated in neoplastic disease, including prostate and breast cancers. In humans, TXA₂ signals through the TPα and TPβ isoforms of the T prostanoid receptor, two structurally related receptors transcriptionally regulated by distinct promoters, Prm1 and Prm3, respectively, within the TP gene. Focusing on TPα, the current study investigated its expression and transcriptional regulation through Prm1 in prostate and breast cancers.
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REVIEWSteroid hormones and carcinogenesis of the prostate: the role of estrogens

Abstract

Int Rev Cytol

Am J Pathol

Toxicology

J Steroid Biochem Mol Biol

Am J Pathol

Urology

Steroids

Crit Rev Oncol Hematol

J Clin Epidemiol

J Steroid Biochem

Am J Pathol

J Nutr

J Nutr

J Biol Chem

J Steroid Biochem Mol Biol

Toxicol Appl Pharmacol

J Urol

J Urol

Biochem Biophys Res Commun

Loss of ERbeta expression as a common step in estrogen-dependent tumor progression

Endocr Relat Cancer

Changes in serum concentrations of conjugated and unconjugated steroids in 40- to 80-year-old men

J Clin Endocrinol Metab

A phase II study of high-dose tamoxifen in patients with hormone-refractory prostate cancer

Clin Cancer Res

The role of steroid hormones in prostate carcinogenesis

J Natl Cancer Inst Monogr

Induction at high incidence of ductal prostate adenocarcinomas in NBL/Cr and Sprague-Dawley Hsd: SD rats treated with a combination of testosterone and estradiol-17 beta or diethylstilbestrol

Carcinogenesis

Spontaneous benign prostatic hyperplasia in the beagle. Age-associated changes in serum hormone levels, and the morphology and secretory function of the canine prostate

J Clin Invest

Role of stromal and epithelial estrogen receptors in vaginal epithelial proliferation, stratification, and cornification

Endocrinology

Diet after diagnosis and the risk of prostate cancer progression, recurrence, and death (United States)

Cancer Causes Control

Neonatal estrogen stimulates proliferation of periductal fibroblasts and alters the extracellular matrix composition in the rat prostate

Endocrinology

Developmental effects of endocrine-disrupting chemicals in wildlife and humans

Environ Health Perspect

Estrogen receptor null mice: what have we learned and where will they lead us?

Endocr Rev

Role of the stromal microenvironment in carcinogenesis of the prostate

Int J Cancer

The importance of stroma in morphogenesis and functional activity of urogenital epithelium

In Vitro

Estrogenic effects on prostatic differentiation and carcinogenesis

Reprod Fertil Dev

Estramustine depolymerizes microtubules by binding to tubulin

Cancer Res

Peripheral hormone levels in controls and patients with prostatic cancer or benign prostatic hyperplasia: results from the Dutch–Japanese case-control study

Cancer Res

Influence of age on steroid concentrations in skin and striated muscle in women and in cardiac muscle and lung tissue in men

J Clin Endocrinol Metab

Role of nerve growth factor-like protein in the paracrine regulation of prostate growth

J Androl

The induction of NB rat prostatic carcinomas

Anticancer Res

Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes

Development

Aromatase and prostate cancer

Minerva Endocrinol

Local aromatase expression in human prostate is altered in malignancy

J Clin Endocrinol Metab

Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study

J Clin Endocrinol Metab

Differential expression of the estrogen receptor beta (ERbeta) in human prostate tissue, premalignant changes, and in primary, metastatic, and recurrent prostatic adenocarcinoma

Prostate

Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts male aging study

J Clin Endocrinol Metab

Estrogens and prostatic disease. International Prostate Health Council Study Group

Prostate

A phase I/II study of high-dose tamoxifen in combination with vinblastine in patients with androgen-independent prostate cancer

Acta Oncol

Physical characteristics and factors related to sexual development and behaviour and the risk for prostatic cancer

Eur J Cancer Prev

The early in utero oestrogen and testosterone environment of blacks and whites: potential effects on male offspring

Br J Cancer

Estrogens and antiestrogens as etiological factors and therapeutics for prostate cancer

REVIEW
Steroid hormones and carcinogenesis of the prostate: the role of estrogens