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Stromal Progesterone Receptors Mediate the Inhibitory Effects of Progesterone on Estrogen-Induced Uterine Epithelial Cell Deoxyribonucleic Acid Synthesis¹

Department of Anatomy (T.K., P.Y., J.R.B., G.R.C.), University of California, San Francisco, California 94143; Department of Cell Biology (J.P.L., B.W.O.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Dr. Gerald R. Cunha, Cancer Research Building, UCSF Mt. Zion Cancer Center, University of California, San Francisco, California. E-mail: gcunha{at}itsa.ucsf

	Abstract

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The role of epithelial and stromal progesterone (P) receptors (PR) in the regulation of uterine epithelial DNA synthesis by P was investigated by analyzing the four types of tissue recombinants prepared with uterine stroma (S) and epithelium (E) from wild-type (wt) and PR knockout (PRKO) mice: wt-S + wt-E, PRKO-S + PRKO-E, wt-S + PRKO-E, and PRKO-S + wt-E. 17-ß estradiol (E₂) stimulated DNA synthesis in all four types of tissue recombinants. On the other hand, P inhibited E₂-induced DNA synthesis only in tissue recombinants prepared with wild-type (PR-positive) stroma (wt-S + wt-E or wt-S + PRKO-E) but not knockout (PR-negative) stroma (PRKO-S + wt-E or PRKO-S + PRKO-E). These results clearly demonstrate that the inhibitory effect of P on uterine epithelial DNA synthesis is mediated by stromal PR. Epithelial PR is neither necessary nor sufficient for P inhibition of E₂-induced epithelial DNA synthesis.

	Introduction

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DEVELOPMENTAL and functional regulation of the uterus involves the action of two major ovarian steroids, 17-ß estradiol (E₂) and progesterone (P). Normal and neoplastic uterine epithelial proliferation (DNA synthesis, mitogenesis, or expression of cell cycle markers such as Ki67) is one of the features controlled by a balance of E₂ and P. Ovariectomized mice have been widely used as a model for studying control of uterine epithelial proliferation by E₂ and P (1, 2). In this system, E₂ alone induces epithelial proliferation, and pretreatment with P inhibits the proliferative effect of E₂ (3, 4). A previous study demonstrated that the inhibitory effect of P on E₂-induced uterine epithelial proliferation was completely blocked by the antiprogestin, RU 486 (5). Thus, P inhibition of epithelial proliferation is elicited not through antagonism of E₂ binding to the estrogen receptor (ER) but instead via the P receptor (PR). This inhibitory effect of P on normal uterine epithelial proliferation serves as the rationale for treating endometrial hyperplasia and adenocarcinoma with progestins (6, 7).

Both E₂ and P elicit their effects via members of the steroid hormone receptor superfamily (ER and PR, respectively) (8). Two isoforms of the ER have been described, ER, the classical ER, and a recently described second form, ERß (9, 10). Although both isoforms are expressed in the uterus (11, 12), E₂ treatment of estrogen receptor- knockout (ERKO) mice does not stimulate uterine epithelial proliferation or transcription of estrogen-responsive genes (13); thus, ER is essential to mediate E₂ signaling in the uterus. The PR is composed of two ligand-binding forms (PR-A and PR-B) differing in size but both derived from one gene (14, 15). Both PR isoforms have been detected in the rodent uterus (16). Steroid autoradiography and immunohistochemistry (IHC) have revealed ER and PR in both uterine epithelial and stromal cells (17, 18, 19). This raises the possibility that effects of E₂ and/or P on UtE could be elicited directly via epithelial ER or PR, respectively, or alternatively via paracrine mechanisms employing ER and/or PR, respectively, in stromal cells. Recent analysis of tissue recombinants prepared with uteri of wild-type and ERKO mice has shown that E₂-induced epithelial mitogenesis is mediated by stromal ER; epithelial ER does not participate in this process (20).

In this study, PR knockout (PRKO) mice have provided the opportunity to analyze the cellular mechanism of P inhibition of uterine epithelial DNA synthesis. PRKO mice lack functional PR as a result of disruption of the PR gene, and therefore reproductive organs in adult female PRKO mice are functionally impaired, leading to infertility (21). PRKO and wild-type mice were used to produce uterine tissue recombinants that lack PR in their epithelium, stroma, or both by using tissue separation and recombination techniques. The objective of this study was to determine whether P-inhibition of E₂-induced uterine epithelial DNA synthesis is mediated via epithelial or stromal PR.

	Materials and Methods

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Animals
All animals were maintained in accordance with the NIH Guide for Care and Use of Laboratory Animals, and all procedures described here were approved by UCSF Animal Care and Usage Committees. Both Balb/c and PRKO mice were used as neonates to obtain uteri. Homozygous PRKO mice were produced as described previously by Lydon et al. (21). Genotypes of pups were determined by a multiplex PCR technique, and only homozygous PRKO female mice with a 129SvEv/C57BL/6 genetic background were used in these experiments.

Tissue separation/recombination and grafting
Procedures for separation and recombination of UtE and stroma have been described (22). Briefly, uteri were dissected free of adherent connective tissue and fat from neonatal (3–14 days) PRKO and Balb/c mice, placed into HBSS, and cut into small pieces. In each experiment, uteri from two to four mice of PRKO and wild-type at the approximate same age were used. Pieces of uteri were enzymatically dissociated by placing them in a solution of 1% trypsin in calcium- and magnesium-free HBSS for 90 min at 4 C. Uteri were cut open, and then stroma and epithelium were physically separated by using fine surgical instruments. Stroma and epithelium were recombined on agar plates and allowed to adhere during overnight culture. In each experiment, at least 12 tissue recombinants were prepared for each category of tissue combinations. After overnight culture, the tissue recombinants were grafted under the renal capsules of female nude mice. In each experiment, at least six nude mice were used as hosts, and each kidney carried three to five tissue recombinants.

Hormone treatment
Renal capsular grafts of tissue recombinants were grown for approximately 1 month, and then all hosts were ovariectomized. Two weeks later, hosts received P and/or E₂, or oil vehicle. All hormone injections were given ip in 0.5 ml peanut oil daily at the following doses: P, 0.5 mg; E₂, 125 ng; E₂ + P, 125 ng E₂ + 0.5 mg P (see Fig. 1). Sixteen and 17 h after the last hormone injection, all hosts were given [³H]-thymidine (1.5 µCi/g body weight in PBS). One hour after the last [³H]-thymidine injection, grafts were removed and fixed in 10% formalin.

View larger version (13K): [in this window] [in a new window]   Figure 1. Experimental protocol. All hormone injections were ip in 0.5 ml oil. P = 0.5 mg P; E2 = 125 ng E2, E2 + P = 125 ng E2 + 0.5 mg P; oil = 0.5 ml oil. 3H-Thy = [3H]-thymidine at 1.5 µCi/g body weight in PBS. Renal capsular grafts of tissue recombinants were grown for approximately 1 month, and then all hosts were ovariectomized. Two weeks later, hosts received P and/or E2 as follows: E2 + P = P on day 1, P + E2 on day 2; E2 group = oil on day 1, E2 on day 2; oil group = oil on days 1 and 2. Sixteen and 17 h after the second hormone treatment, all hosts were given [3H]-thymidine. One hour after the last [3H]-thymidine injection, grafts were removed and fixed in 10% formalin.

For ³H-thymidine autoradiography, tissue sections were dipped in Kodak NTB-2 nuclear emulsion (Rochester, NY) and stored at -80 C. Autoradiograms were exposed for 4 weeks to achieve saturation of nuclear labeling and were developed by standard techniques. Slides were stained with hematoxylin and eosin. Epithelial ³H-thymidine labeling index (LI) was measured as labeled cells per total epithelial cells as described previously (20). Each point is based on analysis of at least nine specimens ( 10,000 epithelial cells per group) from five independent experiments. Data on epithelial DNA synthesis in various groups were analyzed by Student’s t test.

To more clearly show the relationship between PR status and DNA synthesis, tissue recombinants were first stained for PR. Immunohistochemical images were then captured using a Leaf Lumina camera/scanner interfaced to a Macintosh computer. After imaging, coverslips were removed and slides were processed for ³H-thymidine autoradiogrphy, as above. Silver grains from ³H-thymidine autoradiograms were imaged and superimposed on the original PR immunohistochemical images as previously described (20).

	Results

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Four types of tissue recombinants were prepared with uterine stroma (S) and epithelium (E) from wild-type (wt) and PRKO mice: wt-S + wt-E, PRKO-S + PRKO-E, wt-S + PRKO-E, and PRKO-S + wt-E. All four uterine tissue recombinants grew and developed normally (Fig. 2). In homotypic tissue recombinants, epithelium and stroma both were immunostained positive for PR (wt-S + wt-E) (Fig. 2, a and e) or were unstained (PRKO-S + PRKO-E) (Fig. 2, b and f) as was the case for normal and PRKO uteri, respectively. In heterotypic tissue recombinants (wt-S + PRKO-E and PRKO-S + wt-E), only tissue of wt origin stained positive for PR (Fig. 2, c, d, g, and h). ER localization was also analyzed, and ER immunostaining was detected in both epithelium and stroma of all four types of tissue recombinants (data not shown).

View larger version (109K): [in this window] [in a new window]   Figure 2. PR staining and 3H-thymidine labeling in uterine tissue recombinants. Tissue recombinants consisted of wt-S + wt-E (a and e), PRKO-S + PRKO-E (b and f), wt-S + PRKO-E (c and g), and PRKO-S + wt-E (d and h). The experimental protocol is shown in Fig. 1. Tissue recombinants were grown under renal capsule of adult female nude mice for approximately 1 month, and then all hosts were ovariectomized. Two weeks after ovariectomy, hosts were injected E2 only (a–d) or E2 + P (e–h). Nuclei of PR positive cells stain brown, whereas negative nuclei stain blue. In all tissue recombinants, only tissue of wt origin stained positive for PR. Silver grain images (shown as black) of 3H-thymidine autoradiograms were superimposed on the original PR-immunostained images. While high level of 3H-thymidine labeled epithelial cells in all tissue recombinants with E2 treatment (a–d), profound inhibition of epithelial 3H-thymidine labeling was observed in wt-S + st-E and st-S + PRKO-E tissue recombinants (e and g) but not in PRKO-S + PRKO-E (f), and PRKO-S + wt-E tissue recombinants (h) with E2 + P treatment. wt, Wild-type; ko, knockout; E, epithelium; S, stroma.

View larger version (32K): [in this window] [in a new window]   Figure 3. Labeling index in uterine tissue recombinants. Using the treatment protocol described in Fig. 1, epithelial 3H-thymidine labeling index (LI) was measured as labeled cells per total epithelial cells. Each point is based on analysis of at least nine specimens ( 10,000 epithelial cells per group) from five independent experiments. Data on epithelial LI in various groups were analyzed by Student’s t test. All E2-treated tissue recombinants and the E2+P-treated PRKO-S + PRKO-E and PRKO-S + wt-E tissue recombinants had a significantly higher LI (marked with *) than all oil tissue recombinants and the E2+P-treated wt-S + wt-E and wt-S + PRKO-E tissue recombinants (P < 0.01).

	Discussion

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Our results show that response of UtE to P (inhibition of epithelial DNA synthesis) is mediated by stromal PR. Epithelial PR did not play a role in inhibiting E₂-induced uterine epithelial DNA synthesis. Developmental and hormonal response of kidney-grafted tissue recombinants have been extensively studied by our group. It has been well established that tissue recombinants prepared with uterine or other reproductive tract tissues from neonatal animals exhibited the normal adult phenotype morphologically and functionally after 1 month of growth under the renal capsule of adult host animals. For example, the uterine tissue recombinants made with neonatal uteri express appropriate uterine markers such as syndecans (23), msx1, and wnt-5A (24) after 1 month of growth under the renal capsule of mature female hosts. Response of uterine tissue recombinants to E₂ and P is comparable with that of normal host uterine tissue in respect to epithelial DNA synthesis and expression of lactoferrin (20, 25). The power of the tissue recombinants approach for analysis of hormonal response is that the four possible tissue recombinants between wild-type and receptor knockout (KO) epithelium and stroma represent both positive (wt-S + wt-E) and negative (KO-S + KO-E) controls, whereas the two heterotypic tissue recombinants (wt-S + KO-E and KO-S + wt-E) consistently give opposite and mutually confirmatory results. Immunohistochemistry can be used to verify the receptor status of epithelium and stroma of each tissue recombinant (20, 26) to exclude rare technical artifacts due, for example, to stroma being contaminated with homologous epithelium. Given the above considerations our results unequivocally and definitively establish the general concept that epithelial proliferation in hormone target organs is regulated by all classes of steroid hormones (androgen, estrogen, and progestin) through paracrine mechanisms mediated by stromal hormone receptors. Tissue recombinant studies using wild-type and Tfm mice (testicular feminization, a spontaneous androgen receptor mutant) demonstrated that androgens stimulate DNA synthesis of prostatic epithelium via stromal androgen receptors (26). Tissue recombinant studies using ERKO and wild-type mice demonstrated that E₂-induced uterine, vaginal, and mammary epithelial DNA synthesis is mediated by stromal ER (20, 27, 28). The present study clearly shows that P inhibition of E₂-induced epithelial DNA synthesis is mediated by stromal PR. Thus, stimulation as well as inhibition of uterine epithelial DNA synthesis by E₂ and P, respectively, is mediated via stromal ER and PR.

P inhibition of estrogen-induced uterine epithelial proliferation is a general phenomenon occurring in several mammalian species including human (2) and is the rationale for hormonal therapy for proliferative lesions of the endometrium. Etiologic studies show that P is preventive for development of endometrial carcinoma, whereas estrogen promotes this disease (29, 30). P inhibits proliferation of normal human endometrial epithelium, reverses or normalizes both spontaneous and estrogen-induced endometrial hyperplasia, and inhibits growth of human endometrial carcinoma (7, 30). Our tissue recombinant studies in the mouse raise the distinct possibility in humans that paracrine mechanisms may play a role in regulating proliferation of both normal and neoplastic endometrial epithelial cells. Given the generalized alteration in epithelial differentiation during carcinogenesis and the well recognized alterations in carcinoma-associated stromal cells (31, 32, 33, 34, 35), it is likely that development of endometrial carcinoma may entail perturbation of paracrine pathways of growth regulation. Current analysis of heterospecific tissue recombinants composed of normal human or neoplastic UtE plus either wild-type or PRKO uterine stroma will define whether P inhibits proliferation of human UtE via paracrine mechanisms as is the case in the mouse.

Cooke et al. (20, 28) demonstrated the key role of stroma in E₂-induced uterine and vaginal epithelial proliferation. In response to E₂, uterine stroma produces paracrine growth-regulating molecules that stimulate uterine epithelial proliferation. Adapting the model of E₂ effect on uterine epithelial proliferation proposed by Cooke et al. (20), we propose the following models of P inhibition of uterine epithelial proliferation. Mechanistically the growth inhibitory effect of P on uterine epithelial proliferation could result from impaired intracellular synthesis or secretion of E₂-induced paracrine factors (pathway no. 1, Fig. 4). Alternatively, P may elicit the secretion of a paracrine factor that antagonizes the action of E₂-induced paracrine mediators through indirect mechanisms (pathway no. 2, Fig. 4, see discussion below). Another possibility is that the P-induced paracrine mediator is a direct inhibitor of epithelial proliferation (pathway no. 3, Fig. 4). Given these possible mechanistic scenarios, levels of trophic or inhibitory factor transcripts or proteins could be one facet of regulating the bio-availability and biological activity of paracrine mediators. The activation of a trophic or inhibitory paracrine mediator may involve steps such as enzymatic modification (peptide cleavage, phosphorylation or glycosylation, etc.) or regulation of bio-availability of the factor (secretion, binding and/or release from extracellular matrix, etc.). Critical regulatory steps could involve the paracrine mediators themselves, their receptors, binding proteins, or enzymes that modify activity of the molecules involved. Given the scenario that E₂ stimulates UtE proliferation via stromal ER and that P inhibits uterine epithelial proliferation via stromal PR, current knowledge on expression patterns of known molecules is not yet sufficiently detailed to explain the paracrine models suggested by our tissue recombinant studies.

View larger version (91K): [in this window] [in a new window]   Figure 4. Possible mechanisms of E2 and P action on uterine epithelial DNA synthesis. E2-induced proliferative and P-induced inhibitory signals are indicated by light and dark arrows, respectively. E2 binds to stromal ER and generates a paracrine signal which induces DNA synthesis of UtE. P binds to stromal PR, which leads to inhibition of uterine epithelial proliferation. Three possible inhibitory mechanisms are: 1) PR inhibits transcription of ER-dependent paracrine mediators; 2) P-induced gene products antagonize the action of E2-induced paracrine mediators through a variety of indirect mechanisms; and 3) P-induced paracrine mediator is a direct inhibitor of epithelial proliferation such as TGFß.

In this study, we have demonstrated that P inhibition of E₂-induced uterine epithelial DNA synthesis is mediated by stromal PR. Effects of E₂ and P on epithelial function may be elicited by either direct (mediated by epithelial receptors) or indirect (mediated by stromal receptors) mechanisms in different organs. Understanding the cellular mechanism of the actions of P on uterine function will require a determination of whether a given effect of P is mediated either by stromal or epithelial PR.

	Footnotes

 
¹ This work was supported by NIH Grants AG-13784 and HD-07857.

Received April 20, 1998.

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