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Endocrinology Vol. 142, No. 6 2443-2450
Copyright © 2001 by The Endocrine Society

ARTICLES

The Metaplastic Effects of Estrogen on Mouse Prostate Epithelium: Proliferation of Cells with Basal Cell Phenotype1

Gail P. Risbridger, Hong Wang, Mark Frydenberg and Gerald Cunha

Institute of Reproduction and Development, Monash Medical Center, Clayton, Melbourne, Victoria 3168, Australia; Department of Urology, Monash Medical Center, Monash University (M.F.), Clayton, Victoria 3168, Australia; and Department of Anatomy, University of California (G.C.), San Francisco, California 94143

Address all correspondence and requests for reprints to: Dr. Gail Risbridger, Center for Urological Research, Monash Institute of Reproduction and Development, Monash Medical Center, 246 Clayton Road, Clayton, Victoria 3168, Australia. E-mail: gail.risbridger{at}med.monash.edu.au


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The exogenous administration of estrogens to male mice alters the hypothalamic-pituitary-gonadal axis and reduces androgen levels, leading to a regression of the prostatic epithelium. As well, a specific direct response to estrogens is the induction of epithelial squamous metaplasia. The aims of this study were to identify the process by which the prostatic epithelium is transformed in intact adult male mice using the synthetic estrogen, diethylstilbestrol. A comparison of the effects of diethylstilbestrol in the three lobes revealed a hierarchy of response, with the anterior lobe being the most responsive, the dorsolateral lobe less responsive, and the ventral lobe the least responsive. The effect of castration was used to distinguish between the epithelial responses to estrogen administration and androgen deprivation. The results demonstrate that transformation of the epithelium involved proliferation of cells with a basal cell phenotype, the onset of cytokeratin 10 expression, up-regulation of progesterone receptor expression, and loss of the cell cycle inhibitor, p27Kip1 expression; none of these changes was observed after castration. Mice lacking functional estrogen receptor {alpha} failed to respond, demonstrating a requirement for estrogen receptor {alpha} in the epithelium and/or stroma to mediate the proliferative response to estrogen in the prostate gland.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ANDROGENS STIMULATE prostatic growth and prevent apoptosis of prostate. After castration the epithelium regresses, and remaining prostatic epithelial cells are androgen independent, but androgen sensitive. Testosterone replacement regenerates the prostatic epithelium, which is restored to its normal cell number and function (1, 2). Although androgens play a central role in the biology of the prostate, estrogens also regulate prostate growth (3). Estradiol is synthesized in low levels by the testis and locally in the prostate from androgens via the aromatase enzyme (4). It is generally believed that estrogens influence prostatic growth indirectly via effects on the hypothalamic-pituitary-gonadal axis that result in the suppression of testicular testosterone production. However, regression due to systemic androgen withdrawal is followed by metaplastic effects of estrogens and involves squamous transformation of the epithelium. The induction of squamous metaplasia is a specific response to a variety of estrogenic substances, such as 17ß-estradiol, diethylstilbestrol (DES), and zeranol (5, 6, 7), that has been described in a large number of animal species as well as humans, including mice, rats, dogs, beef bulls, monkeys, sheep, and goats (6, 7, 8, 9, 10, 11, 12, 13, 14, 15). Therefore, squamous metaplasia is considered to be a reliable marker or end point for assessing the estrogenic action of DES as well as other estrogenic compounds.

The aims of this study were to determine the sequence of events in response to continuous treatment with DES on mouse prostatic epithelium to understand how the transformation of the epithelium occurs and what cell types are affected. The mouse prostate is a lobular structure, and the response was examined and compared in the anterior, ventral, and dorsolateral prostate lobes. The effect of DES was compared with that of androgen withdrawal after castration of adult wild-type male mice (wt) and to that in mice lacking functional estrogen receptor {alpha} (ER{alpha}; i.e. {alpha}ERKO mice) (16, 17). The results demonstrate that the transformation of the epithelium after estrogen exposure is most marked in the anterior prostate of the mouse and is due to a proliferative response by the basal cells associated with the onset of cytokeratin 10 expression. There is an increase in progesterone receptor immunoreactivity in the luminal secretory cells and loss of expression of p27Kip1. In contrast, regression induced by androgen withdrawal does not elicit these responses in the epithelium. An essential role for ER{alpha} in the proliferative response is implied because mice lacking functional ER{alpha} fail to respond to DES treatment.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animal surgery and hormone treatment
Intact male BALB/c mice were purchased from Central Animals Services, Monash University (Clayton, Australia). {alpha}ERKO mice were obtained by mating mice heterozygous for the ER{alpha} gene disruption as previously described (16, 17). The genotypes of the pups were determined by multiplex PCR, and homozygous males were used for the studies. All animals were maintained in controlled lighting and temperature conditions for the experimental periods and housed in accordance with the National Health and Medical Research Council guidelines for the care and use of laboratory animals.

Adult male BALB/c, {alpha}ERKO mice or wt littermate controls were treated with sc implants of 20-mg pellets containing 2 mg DES and 18 mg cholesterol (18). Groups of three to five wt or {alpha}ERKO animals were studied at intervals of up to 3 weeks of DES treatment. Castration of intact male mice under anesthesia was performed as previously described by Risbridger and collaborators (19).

Immunohistochemistry
A number of histological parameters were used to determine the response to estrogen or the effects of androgen withdrawal by castration using intact adult male mice. Prostate lobes from the various treatment groups were removed by microdissection, and the individual lobes of the prostate (ventral, dorsolateral, and anterior) were identified as previously described (20). Tissues were fixed in Bouin’s solution for 3–5 h, processed, and embedded in paraffin, and sections were stained with hematoxylin-eosin and examined by light microscopy. Identification of basal cells was made by immunolocalization of high mol wt cytokeratin (CKH; cytokeratin 34BE12, DAKO Corp., Carpinteria, CA) and cytokeratin 5 (CK5; Novocastra Newcastle, UK), and keratinization of the epithelium was detected by immunostaining for CK10 (DAKO Corp., Carpinteria, CA). Proliferating cells were identified by immunostaining for proliferating cell nuclear antigen (PCNA; DAKO Corp.); immunostaining for progesterone receptor (PR) was performed using a specific polyclonal antibody (DAKO Corp.), and P27Kip1 was detected using a monoclonal antibody (Transduction Laboratories, Inc., Lexington, KY). Various protocols of pretreatment, with or without antigen retrieval, were employed. Briefly, CK10 immunoreactivity was detected in dewaxed paraffin sections after inactivation of endogenous peroxidase. CK5 and CKH staining were detected after pretreatment with 0.4% trypsin at 37 C for 10 min, followed by inactivation of endogenous peroxidase. PR, PCNA, and p27Kip1 were detected after antigen retrieval in 0.01 M citrate buffer, pH 6.0, for 15 min at 100 C, followed by a period of cooling and inactivation of endogenous peroxidase using 3% hydrogen peroxide. A common procedure for immunostaining was then used for all tissues. Nonspecific binding was blocked using Super Block (Pierce Chemical Co., Rockford, IL), and the sections were incubated with primary antibodies for 1 h at room temperature. After washing, sections were incubated for 30 min with biotinylated horse antimouse IgG (Vector Laboratories, Inc., Burlingame, CA) or biotinylated goat antirabbit IgG (Zymed Laboratories, Inc., San Francisco, CA), followed by incubation with Vectastain Elite ABC kit (Vector Laboratories, Inc.) for 30 min. Visualization of the immunostaining was achieved using 3,3'-diaminobenzidine tetrahydrochloride.

Double staining for specific proteins was conducted using similar protocols, but included the use of a double staining enhancer (Zymed Laboratories, Inc.), strepavidin-alkaline phosphatase, rather than avidin-biotin complex, and staining was visualized with Vector Red (Vector Laboratories, Inc.).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The anterior prostate gland in intact adult wt mice showed the most marked transformation of the epithelium and the induction of squamous metaplasia. Ducts of untreated intact male mice are lined with tall columnar secretory luminal epithelial cells (Fig. 1aGo). A discontinuous layer of basal cells, which exhibit immunostaining for CKH, was present beneath the luminal cells (Fig. 1bGo). CK10 was not detected by immunocytochemistry in either the luminal or basal cells (Fig. 1cGo) of untreated mice. After 3 weeks of treatment with DES, anterior prostatic epithelium of wt mice had undergone squamous metaplasia (Fig. 1dGo); the effect was uniformly observed throughout the gland. Immunostaining with anti-CKH revealed an increase in the number of basal cells, which formed multiple cell layers (Fig. 1eGo). The thickened metaplastic epithelium was also positive for CK10 (Fig. 1fGo).



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  		Figure 1. Effects of DES on anterior, dorsolateral, and ventral lobes of the prostate gland in adult male mice. Groups of mice were treated with DES, and after 3 weeks, the histology of the prostate lobes was examined together with the expression of CKH and CK10 immunoreactivity. a–c, Hematoxylin-eosin-, CKH-, and CK10-stained sections of anterior prostate in wt untreated mice. After 3 weeks of DES administration to wt mice, the stratification of the epithelium was identified by hematoxylin-eosin (d) and CKH and CK10 expression (e and f). The corresponding sections from the dorsolateral and ventral lobes of the prostate are shown in g–l and m–r, respectively. g, h, and i, respectively, show hematoxylin-eosin-, CKH-, and CK10-stained sections of dorsolateral prostate in wt untreated mice; j, k, and l, respectively, show the corresponding sections from regions of tissue from mice treated with DES. m, n, and o, respectively, show hematoxylin-eosin-, CKH-, and CK10-stained sections of ventral prostate in wt untreated mice; p, q, and r, respectively, show the corresponding sections from regions of tissue from mice treated with DES. Bar, 50 µm; magnification, x360.

 
Squamous metaplasia was also observed in the dorsolateral prostate and ventral prostate lobes. However, in contrast to the uniform transformation of the anterior prostate epithelium, the dorsolateral prostate and ventral prostate showed only sparse regions of epithelial squamous cells. Figure 1Go shows ductal tissues from untreated mice with a discontinuous layer of basal cells and no CK10 immunoreactivity in the epithelial layer of dorsolateral prostate and ventral prostate lobes (Fig. 1Go, g–i and m–o, respectively). After DES treatment, regions of dorsolateral prostate and ventral prostate lobes where the transformation was most marked were seen (Fig. 1Go, j–l and p–r). An increased prominence of the basal cell layer was associated with the onset of CK10 expression in both lobes (Fig. 1Go, l and r). In contrast to the anterior prostate, where the response was uniform, only patchy regions of response were observed in the dorsolateral prostate and ventral prostate. Hence, a comparison of the effects of DES in the three lobes revealed a hierarchy of response, with the anterior prostate being the most responsive, the dorsolateral prostate less responsive, and the ventral prostate the least responsive.

The process by which the epithelium undergoes squamous metaplasia was determined using the anterior prostate of wild-type mice and tissues obtained after 7, 10, and 14 days of DES treatment. Sections of anterior prostate tissue from untreated mice showed the discontinuous basal cell layer that was CK5 positive, but CK10 negative (Fig. 2Go, a and b); there were few proliferating cells as identified by PCNA immunoreactivity (Fig. 2cGo), and no cells were positive for PR (Fig. 2dGo). After 7 days of DES treatment the basal cells formed a continuous layer underneath the luminal cells, as demonstrated by immunostaining with anti-CKH (not shown) and CK5 (Fig. 2eGo). Some of the basal cells also expressed CK10 at 7 days of DES treatment (Fig. 2fGo). A few cells were positive for PCNA (Fig. 2gGo), and PR expression was detected for the first time (Fig. 2hGo). At 10 days of DES treatment the continuous basal cell layer began to stratify. Focal pockets of stratified basal epithelial cells emerged from the basal cell layer and expressed CKH (data not shown) and CK5 and CK10 (Fig. 2Go, i and j), an identified subset of the cells in the most basal aspect of the epithelium was positive for PCNA (Fig. 2kGo), and immunoreactivity for PR was readily detected (Fig. 2lGo). At 14 days of DES treatment multiple layers of squamous cells were present underlying the original columnar luminal epithelial cells. These stratified squamous cells expressed CKH (data not shown) and CK5 and CK10 (Fig. 2Go, m and n), and a subset of cells in this layer was positive for PCNA (Fig. 2oGo). As the squamous cells emerged, many epithelial cells in mitosis were seen in this layer (Fig. 2nGo, marked with arrow). In the adluminal layer of cells, PR protein was detected (Fig. 2pGo). Similar findings were apparent at 21 days, and the ducts of the anterior prostate were distended with multiple layers of stratified squamous cells (data not shown).



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  		Figure 2. The time course of the changes to the anterior prostate epithelium during 7, 10, and 14 days of exposure to DES. Compared with untreated tissue, there was a progressive change in the epithelium over 7, 10, and 14 days in terms of CK5 immunoreactivity, as shown in a and e, i, and m, respectively. The corresponding changes in CK10 expression are shown in b and f, j, and n; those in PCNA expression are shown in c and g, k, and o, respectively, and those in progesterone receptor localization are shown in d and h, l, and p. Arrows indicate cells in mitosis. Bar, 50 µm; magnification, x400.

 
After 21 days of DES treatment, double staining for PCNA and CKH confirmed that the proliferating cells also expressed CKH and thus were basal cells (Fig. 3aGo). Double staining for PR and CKH demonstrated that much of the PR staining was localized to CKH-negative columnar epithelial cells, which lay above the emerging squamous layer after 21 days of DES (Fig. 3bGo). In the epithelium of untreated mice, a number of cells were identified that express CKH and p27Kip1 proteins (Fig. 3cGo) throughout the epithelial regions of the tissue. After DES treatment, cells that are positive for p27Kip1 were not detected in the squamous epithelium (Fig. 3dGo).



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  		Figure 3. a, Double staining for CKH (pink color) and PCNA (brown nuclear color); b, double staining for CKH (pink cytoplasmic color) and PR (brown nuclear color) in tissues from mice treated with DES for 21 days. The expression of p27Kip1 was readily detected in the epithelium of anterior prostate from untreated male mice as shown in c, but was not observed in the squamous epithelial cell layer after DES treatment (d). Bar, 50 µm; magnification, x400.

 
To clarify whether the response to DES was due to a systemic effect on androgen levels, mouse prostates were studied for up to 21 days after castration. Castration elicited a gradual increase in the prominence of the basal cell layer so that full regression was associated with a continuous single layer of CKH-positive basal cells (Fig. 4Go, a–c). However, at 7–21 days after castration CK10 remained undetectable (Fig. 4Go, d–f), PCNA-positive epithelial cells (luminal or basal) were rarely observed (Fig. 4Go, g–i), and up-regulation of PR expression was not recorded (Fig. 4Go, j–l). Thus, multilayering of the basal cell layer, the expression of CK10, the increase in PCNA-positive cells in the basal aspect of the multilayers, and the up-regulation of PR expression in the adluminal cells of the multilayer were specific effects of estrogen treatment.



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  		Figure 4. The effect of castration for up to 21 days is shown in Fig. 4Go. The pattern of expression of CKH over 7, 14, and 21 days is shown in a–c, that for CK10 is shown in d–f, that for PCNA is shown in g–i, and for progesterone receptor in j–l. The positive staining of basal cells with CKH appeared to be more prominent as the epithelium regressed due to androgen withdrawal (a–c). No positive immunoreactivity for CK10 was observed at any time interval (d–f). A few PCNA positively stained cells were present in the prostate epithelium of castrated mice (g–i). No progesterone receptor expression was detected in the epithelium (j–l). Bar, 50 µm; magnification, x400.

 
A direct effect of DES via the ER{alpha} was implied because the changes to the epithelium that we described in detail above did not occur in the {alpha}ERKO mice treated with DES for 3 weeks. After DES administration, the epithelium was not transformed (Fig. 5Go, a and b), and multilayering of the basal cell layer and the expression of CK10 were not observed (Fig. 5Go, c and d). Cells positive for p27Kip1 protein were detected in the epithelium before and after DES treatment (Fig. 5Go, e and f), and PR expression in prostatic epithelial cells was not up-regulated by DES administration to {alpha}ERKO mice (Fig. 5Go, g and h).



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  		Figure 5. Intact {alpha}ERKO mouse anterior prostate was not responsive to DES as shown by comparing tissues from untreated (a and c, e, and g) and treated (b and d, f, and h) mice. After 3 weeks of DES treatment the epithelium does not become squamous (a and b); there is no onset of CK10 expression in the basal cell layer (c and d), no loss of p27Kip1 expression in the epithelium (e and f, arrows), and no up-regulation of progesterone receptor expression (g and h). Bar, 50 µm; magnification, x400.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study demonstrated that the estrogen action on the mouse anterior prostate epithelium resulted in squamous metaplasia, which was characterized by multilayering of the epithelial basal cells and the onset of CK10 expression. The stratified squamous cells contained a basally located layer of proliferating epithelial cells that lacked expression of the cell cycle inhibitor p27Kip1. The adluminal cell layer was negative for CK5 or CKH expression, but showed the presence of PR immunoreactivity after DES treatment. These responses were not observed when the {alpha}ERKO mouse was treated with DES, consistent with a requirement for a functional ER{alpha} in the epithelium and/or stroma to mediate the estrogenic response in the adult mouse prostate.

The ventral prostate is the most commonly examined prostatic lobe in studies using rats and mice. During postnatal development of the rat prostate Prins and co-workers reported that neonatal exposure to estrogens altered prostatic growth and epithelial cell differentiation that led to increased incidence of prostatic metaplasia, dysplasia, and tumor formation with aging (21, 22). Although the greatest response was observed in the ventral prostate, the dorsal and lateral lobes were also affected. vom Saal and colleagues (23) reported dose-related effects of estradiol or DES on prostatic size in mice and specifically that low doses of estrogen significantly increased the area of the dorsal, but not ventral, region of budding during development of the urogenital system in male rats (24). After puberty, when maturation of the gland is complete, the administration of estrogen results in the induction of squamous metaplasia. This response is common to a large range of mammalian species regardelss of differences in the anatomical structure of the glands (6, 7, 8, 9, 10, 11, 12, 13, 14, 15). Squamous metaplasia is considered to be a reliable end point to assess estrogenic action, including 17ß-estradiol, DES, and zeranol (5, 6, 7).

Our studies identify a hierarchy of metaplastic response to estrogen in the mouse prostate lobes and show that the anterior prostate is the most sensitive, the dorsolateral prostate less sensitive, and the ventral prostate the least sensitive to DES. The effect of DES on the anterior prostate was apparent throughout the tissue, but only limited regions of tissue from dorsolateral prostate and ventral prostate showed squamous changes in this study. Thus, in contrast to the anterior prostate, the effect of DES on the other lobes was not uniform. Although this action of DES on the individual lobes may be time and dose related, the data are consistent with previous reports of estrogen binding (25) and immunohistochemical staining for ER{alpha} in these lobes of the prostate (26). The anterior prostate exhibits intense ER{alpha} immunostaining and is the most sensitive lobe to estrogenic stimulation. Thus, the anterior prostate is particularly appropriate for the study of estrogen action in mice.

This study describes the effects of DES that are different from those of castration- induced atrophy of the epithelium, because prostatic atrophy also occurs when DES is given to intact male mice. Specific effects of DES include initiation of proliferation in the basal layer of the epithelium in cells that have a basal cell phenotype as judged by the expression of CKH.

In the untreated males numerous prostatic epithelial cells were positive for the cell cycle inhibitor p27Kip1. After DES treatment, a continuous layer of proliferating basal cells emerged that were positive for PCNA, whereas p27Kip1positive cells were not detected in the multilayered epithelium. The proliferative activity of cells in the basal cell layer is consistent with a previous report that approximately 70% of labeled cells in normal and hyperplastic acini of the human prostate were of the basal cell phenotype (27). More recently, de Marzo and colleagues (28) provided anatomical evidence for the presence of a transiently proliferating population of cells in the basal cell layer and identified this population of cells by the down-regulation of the cyclin-dependent kinase inhibitor p27Kip1. They postulated that upon receipt of the appropriate mitogenic signal, cells in this population are competent for rapid entry into the cell cycle. Our results suggest that DES may be one of the mitogenic signals that induce proliferation of cells that have lost expression of p27Kip1. Estrogens have been implicated in prostate carcinogenesis and tumor progression, and if p27Kip1 plays a major role in regulating cell cycle events in malignant prostate epithelial cells, as suggested previously (28), a link between estrogen/DES action and the development of a malignant epithelial cell phenotype may be revealed in further investigations.

We observed estrogen-induced up-regulation of PR expression in the prostate, which is dependent upon the presence of a functional ER{alpha}. We previously reported that mice lacking a functional ERß show squamous metaplasia in response to DES administration (26). Therefore, the essential role for ER{alpha}, in terms of induction of squamous metaplasia, has been confirmed. The action of DES on the anterior prostate was similar to that of estrogen action on mouse vagina (29). Estrogens regulate vaginal development and specifically promote vaginal epithelial cell proliferation and cytodifferentiation, events that require the presence of a functional ER{alpha}. Estrogen administration to ovariectomized female mice resulted in proliferation of basal epithelial cells and differentiation of a cornified CK10-positive vaginal epithelium. In the vaginal model, epithelial proliferation was elicited via a paracrine stromal-epithelial interaction in which ER{alpha} was required in the stromal cells. Vaginal epithelial cornification required ER{alpha} in the epithelial cells. In the prostate we showed the requirement for stromal and epithelial ER{alpha} for a full response to estrogen (26). Thus, in both vaginal and prostate tissues the simultaneous presence of stromal and epithelial ER{alpha} is required for estrogen action.


   Acknowledgments
 
The authors gratefully acknowledge the gift of {alpha}ERKO mice from Prof. Dennis Lubahn, and the assistance of Dr. Ghanim Almahbobi in the preparation of the manuscript.


   Footnotes
 
1 This work was supported by National Health and Medical Research Council funding (to G.P.R.) in 1997 and by grants DK-47517, DK-52708, CA-64872, and CA-59831 (to G.C.). Back

Received September 22, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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