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Department of Physiology, Research Centre for Endocrinology and Metabolism, Göteborg University, Medicinaregatan 1F, S-413 90 Göteborg, Sweden (H.W., J.K., J.T.) and Department of Internal Medicine, Research Centre for Endocrinology and Metabolism, Sahlgrenska Hospital, S-413 45 Göteborg, Sweden (O.G.P.I.)
Address all correspondence and requests for reprints to: Jan Törnell, Department of Physiology, Göteborg University, Medicinaregatan 1F, S-413 90 Göteborg, Sweden. E-mail: jan.tornell{at}ss.gu.se
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The level of PRL increases with age (2, 3), coinciding with development of prostate hyperplasia. PRL is a multifunctional pituitary hormone involved in a wide variety of physiological processes. In vertebrates, many diverse effects have been attributed to PRL, including reproduction, immune response, osmoregulation, cellular proliferation, and differentiation (4, 5). The most studied functions of PRL in mammals are the effects on mammary gland development, mammary growth, and stimulation of transcription of milk protein genes (6). The prostate has PRL receptors (PRLR) (7, 8) and both trophic and differentiating effects have been observed (9).
The role for PRL in disease of the prostate is, however, not clear. In the human, conflicting results concerning the PRL levels in patients with prostate hyperplasia have been reported demonstrating both increased serum levels (10, 11), unchanged levels (12), and increased levels only in patients with prostate cancer (12). These discrepancies may partially be explained by the recent observation that PRL is locally produced in the human prostate (13). A possible effect of PRL on the prostate is also suggested by the observation that hypophysectomy has an additive effect when combined with castration and adrenalectomy compared with only castration and adrenalectomy in patients with metastatic prostate cancer (14).
Androgens are known to be very important for development of the prostate gland. However, the level of testosterone is decreasing with age (15, 16), indicating that other factors than androgens could be important for development of prostate hyperplasia.
The aim of the present study was to study the effects of increased levels of PRL on the prostate gland by creating PRL-transgenic mice. We now report that PRL-transgenic mice develop dramatic prostate enlargement.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). The
Mt-1-rPRL fragment was excised by digestion with BstEII,
located in the Mt-1 promoter, and BamHI located 3' in the
polylinker of pGEM-7Z.
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To identify transgenic animals, DNA was extracted from 0.5 cm sections of tails from 3-week-old mice by digestion with 400 mg of proteinase K in 0.6 ml of 1 M urea, 100 mM NaCl, 50 mM Tris HCl (pH 8.0), 10 mM EDTA, 0.5% SDS at 55 C for 16 h. The digested tails were frozen for 2 h in -70 C, then precipitated with isopropanol and washed with ethanol. The presence of the Mt-1 rPRL transgene was detected with PCR (94 C for 5 min and 30 cycles of sequential incubations at 94 C for 30 sec, 54 C for 30 sec, and 72 C for 120 sec) using one primer located in the Mt-promoter (5'-GCGAATGGGTTTACGGA-3') and one in the rPRL gene (5'CCATGAAGCTCCTGATGCT-3'). Mice that had integrated the bGH transgene were identified with PCR (the same incubation conditions as for rPRL) using the same Mt-promoter primer and one primer located in the bGH gene (5'-CTCCAGGGACTGAGAACA-3'). The animals were housed under standard conditions and tap water and pelleted food were freely available.
RNA analysis
Total RNA was isolated from frozen tissues by acid guanidinium
thiocyanate-phenol-chlorophorm extraction described by Chomczynski and
Sacchi (21). Specific RNA was analyzed using an RT-PCR assay. The RT
reaction was performed with 0.5 µg RNA as a template in the presence
of 0.25 µg oligo-(deoxythymidine) primer (Promega), 5 U AMV-RT
(Promega), 20 U RNAsin (Promega), and dNTP (Pharmacia) at a final
concentration of 1 mM per nucleotide. RT buffer (50
mM Tris-HCl; pH 8.3, 50 mM KCl, 10
mM MgCl2, 0.5 mM spermidine, and 10
mM DTT) was added to a total volume of 20 µl. After
denaturation at 70 C for 5 min and annealing in room temperature for 10
min, the elongation was carried out for 60 min at 42 C. The RT reaction
was terminated by heat inactivation (95 C for 7.5 min). Rat
PRL-specific RNA was analyzed by amplifying an aliquot of complementary
DNA (cDNA) by PCR (94 C for 5 min and 30 cycles of sequential
incubations at 94 C for 30 sec, 60 C for 30 sec and 72 C for 120 sec)
using a sense primer located in exon 4 (5-TCCATGAAGCTCCTGATGCT-3') and
an antisense primer located in exon 5 (5-GGATGGAAGTTGTGACCA-3')
specific for rat PRL (see Fig. 3). The PCR products were analyzed by
electrophoresis in 1% agarose gel. The size of the fragment amplified
from spliced RNA should be 152 bp and that from unspliced RNA or
contaminating DNA 1252 bp. The fragments were transferred to Hybond-N
nylon membranes (Amersham) and the membranes were baked in 80 C for
2 h and prehybridized in hybridization buffer (0.2 M
NaH2PO4, pH 7.4, 8% SDS, 1 mM
EDTA, 1% BSA fraction V) at 60 C for 2 h. As probe, a 823 bp
PstI fragment (22) containing the rat PRL cDNA was used,
labeled with a random priming kit (Amersham) and P32dCTP.
The hybridization was carried out in the same buffer at 60 C for 12–16
h and washed with 2 x SSC, 0.5% SDS at 60 C for 1–2 h and with
0.1 x SSC, 0.1% SDS at 60 C for 0,5–2 h.
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Specific RNA for the long form of the mouse PRL receptor was amplified by PCR (94 C for 5 min and 30 cycles of sequential incubations at 94 C for 30 sec, 56 C for 30 sec and 72 C for 120 sec.) using a sense primer located in the extracellular part of the receptor (5'-GACTCGCTGCAAGCCAGACC-3') and an antisense primer located in the intracellular part of the long form of the receptor (5'-TGACCAGAGTCACTGTCAGG-3'). The size of the fragment amplified from spliced RNA should be 440 bp. The transfer, hybridization, probe labeling, and washing were carried out as above. An EcoRI-XhoI fragment of the plasmid 4A314 (R. Ball, Basel, Switzerland, unpublished data) containing the long form of the mouse PRL receptor cDNA was used as a probe.
DNA content analysis
Total nucleic acids (TNA) were extracted by homogenization of
frozen tissues in 1% SDS, 20 mM Tris-HCl (pH 7.5), and 4
mM EDTA, followed by a 45-min digestion with proteinase-K
in 45 C and extraction with phenol-chloroform (23). The DNA content in
the TNA preparations were measured with a fluorescence
spectrophotometer (450 nm excitation and 555 nm emission) after
addition of Hoecht’s dye H 33258 (0.2 µg/ml in 2 M NaCl,
1 mM EDTA and 10 mM Tris, pH 7.4).
Measurement of rat PRL
Serum levels of rat PRL were measured by rat PRL RIA (Amersham
UK) according to a protocol from the manufacturer. Mouse PRL does not
cross-react with the antibody raised against rat PRL according to the
manufacturer. Serum was either collected from the mouse tail in heparin
coated glass capillaries or by heart puncture in heparin coated
syringes when killed. All samples were analyzed in duplicates.
Measurement of IGF-I
The IGF-I concentration in serum was determined by a RIA after
acid ethanol extraction according to the manufacturer’s protocol
(Nicols Institute Diagnostics, San Juan Capistrano, CA) in a single
assay.
Measurement of testosterone
Serum testosterone was measured by RIA according to the
manufacturer’s protocol (ICN Biomedicals, Inc., Costa Mesa, CA)
Histology
Tissue pieces were fixed in 4% paraformaldehyde in PBS (pH 7.4)
overnight or longer, dehydrated, and embedded in paraffin. Sections
were stained in hematoxylin/eosin.
Statistics
Statistical differences were calculated using the Wilcoxon rank
sum test. Significance levels less than 0.05 were considered
significant. Values are given as mean ± SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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was
microinjected into 250 mouse zygotes obtained after superovulation and
implanted into 9 foster mothers resulting in 40 newborn mice. Three
mice were identified as carrying the Mt-rPRL construct using PCR
analysis. The founder animals, two females and one male, were mated for
establishing lines of transgenic mice. Transgenic lines were
successfully established from the female founder animals mated to
normal male mice. Heterozygot male offspring from a bGH transgenic founder were used. Male mice from this line have serum levels of bGH higher than 5 times the normal peak values in mice (24).
The transgenic mice had elevated serum levels of rPRL
The rPRL levels in the founder animals were measured by RIA at 35
days of age. One female founder (L1) had very high levels of PRL (470
ng/ml), and the other female founder (L2) expressed the transgene at
lower levels (11 ng/ml). The rPRL levels in the male founder (L3) was
32 ng/ml (no line was established from this founder due to
infertility). Rat PRL levels were also measured in all the animals
included in the study when killed (Table 1). Serum levels of rPRL were stable over
the life span of the animals. Offspring generated from transgenic line
L1 showed consistently high serum rPRL-levels, whereas offspring
generated from L2-line expressed the transgene at lower levels (Table 1).
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). On average, the
dorso-lateral lobes from the prostate were 20 times larger (wet weight)
than the controls, and the ventral parts were 9 times larger (wet
weight) (Table 1). The bGH transgenic mice had 1,6-times larger
dorso-lateral lobes of the prostate glands (Table 1) and also increased
body weight (1.4 times larger than controls, data not shown). In
contrast, the body weight of the PRL transgenic mice were not increased
(data not shown). The DNA content in the prostate glands were measured in rPRL transgenic animals (n = 5) and controls (n = 5) when killed. The total DNA in the dorso-lateral lobe was increased 4.7 times (155 ± 34 µg DNA/prostate lobe vs. 33 ± 5 µg DNA/prostate lobe in the controls, P < 0.01) and in the ventral lobe 4.2 times (96 ± 11 µg DNA/prostate lobe vs. 23 ± 5 µg DNA/prostate lobe in the controls, P < 0.01).
Histologically, in contrast to controls (Fig. 2a) all prostates from PRL transgenic
mice showed hyperplasia and glands distended by secretion mingled with
nests of small glands (Fig. 2b). The amount of stroma was increased in
the rPRL transgenic animals compared with controls (Fig. 2, a and
b).
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, c and d).
The rPRL transgene, the endogenous mPRL gene and the PRLR were
expressed in the prostate gland
Specific messenger RNA (mRNA) for the rPRL transgene was detected
in both the dorso-lateral part of the prostate and in the ventral lobe
(Table 2) in all of the lines (L1, L2,
and L3) measured with RT-PCR. In normal and transgenic animals,
expression of the mouse PRL gene was detected in all parts of the
prostate gland (Table 2). Also, PRLR-specific mRNA was detected in the
dorso-lateral lobe and the ventral lobe of the prostate (Table 2).
Several different tissues were analyzed for the presence of mRNA
corresponding to rPRL using a RT-PCR assay. The primers were selected
in a way that the PCR reaction could not amplify cDNA corresponding to
expression of the mouse PRL gene. The transgene was expressed in the
liver, kidney, pancreas, seminal vesicles, testis, thymus, and the
prostate gland (Fig. 3).
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). The testosterone levels among the
individual rPRL transgenic mice could not be correlated to the prostate
weight in neither the dorso-lateral lobe nor the ventral lobe (r =
0.50 and r = -0.20, respectively P > 0.05).
The IGF-I levels were elevated in the rPRL- and the bGH transgenic
animals compared with controls (Table 1).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The enlargement of the prostate in the transgenic animals was a result of increased secretion of the prostate glands but also a true hyperplasia because the number of cells were increased by 4- to 5-fold. The proportion of connective tissue compared with epithelial cells were increased in the PRL transgenic animals, thus resembling the histological finding in benign prostate hyperplasia (BPH) of man (25). In the PRL transgenic animals, the dorso-lateral part of the prostate, corresponding to the part of the human prostate where BPH develops (26), showed a greater increase in weight and DNA content than the ventral part.
The effect of the PRL could either be direct mediated via PRLR in the prostate gland (7, 8), indirect via receptors (for references, see 5) in other organs (e.g. by stimulation of testosterone synthesis from the testis; 27) or a combination of both.
The importance of androgens for growth of the prostate gland is indeed unquestionable, and removal of androgens from patients with prostate cancer has beneficial effects. In the prostate, PRL can increase cytosol and nuclear androgen receptor levels in the rat (28) and also increase the uptake of testosterone in man (29), suggesting that PRL can increase the tissue concentration or sensitivity for testosterone. However, long-term elevation of testosterone in rats does not result in an increased growth of the prostate above normal size (30), not supporting that elevated testosterone levels are the major cause of the enlargement and hyperplasia in the PRL transgenic mice in this study. Moreover, testosterone levels in the PRL transgenic mice could not be correlated to the prostate weight.
The PRL-transgenic mice had elevated IGF-I levels. However, serum IGF-1 is not likely to be the major mediator of the effects of PRL because mice transgenic for bGH with normal or slightly enlarged prostate glands in relation to body weight (31 and the present study), had at least as high serum IGF-I levels as the PRL-transgenics.
Because PRL was produced in the normal prostate gland (13 and the present study) and rat PRL was expressed in our transgenic model, it could be possible that PRL acts in a paracrine or autocrine fashion to stimulate the prostate growth in addition to an endocrine mechanism of action. This hypothesis needs to be further clarified in future studies.
The additional beneficial effects of hypophysectomy combined to orchidectomy and adrenalectomy compared with orchidectomy and adrenalectomy alone on the growth of prostate cancer metastases in man suggest that some pituitary hormone(s) is involved in stimulation of the prostate gland. Experiments using isografted pituitaries have shown a stimulation of prostate growth (32). However, isografts also secrete other pituitary hormones, e.g. GH (33). GH is structurally related to PRL and both the GH-receptor and the PRLR belong to the cytokine receptor superfamily (34). The prostate gland of mice transgenic for bovine GH (bGH) were slightly larger than in controls (31 and the present study). In contrast to studies using pituitary isografts, all effects observed in PRL transgenic animals can be attributed directly or indirectly to the elevated PRL levels.
PRL transgenic animals may serve as a useful model for studying prostate hyperplasia. In addition to previously described transgenic models using expression of int-2 (35) and large-T (36, 37), the present model represents a hormone-dependent hyperplasia and might therefore be closer to the human patophysiology. Another similarity to BPH in man is that the stroma compartment of the prostate in the rat PRL transgenic mice is enlarged, in contrast to the int-2 and large T models (35, 36, 37).
In the human, the influence of PRL on prostate growth is not clear, but the present study suggests that the question whether PRL is an important factor for development of prostate hyperplasia in man should be addressed.
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Acknowledgments |
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Footnotes |
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Received April 15, 1997.
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S. J. McPherson, H. Wang, M. E. Jones, J. Pedersen, T. P. Iismaa, N. Wreford, E. R. Simpson, and G. P. Risbridger Elevated Androgens and Prolactin in Aromatase-Deficient Mice Cause Enlargement, But Not Malignancy, of the Prostate Gland Endocrinology, June 1, 2001; 142(6): 2458 - 2467. [Abstract] [Full Text] [PDF]
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J. B. Kline, D. J. Moore, and C. V. Clevenger Activation and Association of the Tec Tyrosine Kinase with the Human Prolactin Receptor: Mapping of a Tec/Vav1-Receptor Binding Site Mol. Endocrinol., May 1, 2001; 15(5): 832 - 841. [Abstract] [Full Text]
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 G. UNTERGASSER, H. RUMPOLD, E. PLAS, S. MADERSBACHER, and P. BERGER A low-molecular-weight fraction of human seminal plasma activates adenylyl cyclase and induces caspase 3-independent apoptosis in prostatic epithelial cells by decreasing mitochondrial potential and Bcl-2/Bax ratio FASEB J, March 1, 2001; 15(3): 673 - 683. [Abstract] [Full Text] [PDF]
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 K. A. McClellan, F. G. Robertson, J. Kindblom, H. Wennbo, J. Törnell, B. Bouchard, P. A. Kelly, and C. J. Ormandy Investigation of the Role of Prolactin in the Development and Function of the Lacrimal and Harderian Glands Using Genetically Modified Mice Invest. Ophthalmol. Vis. Sci., January 1, 2001; 42(1): 23 - 30. [Abstract] [Full Text]
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 F. Van Coppenolle, C. Slomianny, F. Carpentier, X. Le Bourhis, A. Ahidouch, D. Croix, G. Legrand, E. Dewailly, S. Fournier, H. Cousse, et al. Effects of hyperprolactinemia on rat prostate growth: evidence of androgeno-dependence Am J Physiol Endocrinol Metab, January 1, 2001; 280(1): E120 - E129. [Abstract] [Full Text] [PDF]
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K. Dorshkind and N. D. Horseman The Roles of Prolactin, Growth Hormone, Insulin-Like Growth Factor-I, and Thyroid Hormones in Lymphocyte Development and Function: Insights from Genetic Models of Hormone and Hormone Receptor Deficiency Endocr. Rev., June 1, 2000; 21(3): 292 - 312. [Abstract] [Full Text]
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H. Huang and D. D. Brown Overexpression of Xenopus laevis growth hormone stimulates growth of tadpoles and frogs PNAS, January 4, 2000; 97(1): 190 - 194. [Abstract] [Full Text] [PDF]
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T. J. Ahonen, P. L. Härkönen, J. Laine, H. Rui, P. M. Martikainen, and M. T. Nevalainen Prolactin Is a Survival Factor for Androgen-Deprived Rat Dorsal and Lateral Prostate Epithelium in Organ Culture Endocrinology, November 1, 1999; 140(11): 5412 - 5421. [Abstract] [Full Text]
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 C. J. Phelps and D. L. Hurley Pituitary Hormones as Neurotrophic Signals: Update on Hypothalamic Differentiation in Genetic Models of Altered Feedback Experimental Biology and Medicine, October 2, 1999; 222(1): 39 - 58. [Abstract] [Full Text]
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I. Leav, F. B. Merk, K. F. Lee, M. Loda, M. Mandoki, J. E. McNeal, and S.-m. Ho Prolactin Receptor Expression in the Developing Human Prostate and in Hyperplastic, Dysplastic, and Neoplastic Lesions Am. J. Pathol., March 1, 1999; 154(3): 863 - 870. [Abstract] [Full Text] [PDF]
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R. W. Steger, V. Chandrashekar, W. Zhao, A. Bartke, and N. D. Horseman Neuroendocrine and Reproductive Functions in Male Mice with Targeted Disruption of the Prolactin Gene Endocrinology, September 1, 1998; 139(9): 3691 - 3695. [Abstract] [Full Text] [PDF]
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