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Endocrinology Vol. 138, No. 10 4435-4444
Copyright © 1997 by The Endocrine Society

ARTICLES

Combined Effects of Dehydroepiandrosterone and EM-800 on Bone Mass, Serum Lipids, and the Development of Dimethylbenz(A)Anthracene-Induced Mammary Carcinoma in the Rat1

Shouqi Luo, Antigone Sourla, Claude Labrie, Alain Bélanger and Fernand Labrie

Medical Research Council Group in Molecular Endocrinology, CHUL Research Center and Laval University, Québec G1V 4G2, Canada

Address all correspondence and requests for reprints to: Prof. Fernand Labrie, Laboratory of Molecular Endocrinology, CHUL Research Center, 2705 Laurier Boulevard, Québec G1V 4G2, Canada.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Although treatment with dehydroepiandrosterone (DHEA) and the antiestrogen EM-800 alone decreased dimethylbenz(A)anthracene (DMBA)-induced mammary tumor incidence from 95% to 57% and 38%, respectively, approximately 9 months after DMBA administration, only two tumors developed in the group of animals that received the combination of DHEA and EM-800, and these two tumors disappeared before the end of the experiment (P < 0.01 vs. DHEA or EM-800 alone). Average tumor number per tumor-bearing animal as well as average tumor area per tumor-bearing animal were further decreased in animals that received the combination therapy compared with the effect of each treatment alone (P < 0.01). DHEA induced 6.9% (P < 0.01), 10.6% (P < 0.05), and 8.2% (P < 0.01) increases in bone mineral density of total skeleton, lumbar spine, and femur, respectively. The addition of EM-800 to DHEA did not affect the enhancing effect of DHEA on bone mass. The combination of the two drugs had important inhibitory effects on the urinary excretion of calcium and phosphorus as well as on the urinary hydroxyproline/creatinine ratio. Serum total alkaline phosphatase was stimulated by DHEA. Treatment with EM-800 decreased both serum triglyceride and cholesterol levels, whereas DHEA had an inhibitory effect on serum triglycerides. Although treatment with EM-800 caused a marked atrophy of the mammary gland, DHEA alone reduced lobular hyperplasia seen in aged intact rats while causing an androgen-specific stimulation of the same structures in animals already receiving the antiestrogen EM-800. The combination of DHEA and EM-800 lowered ovarian weight by 24% (P < 0.01) and decreased serum estradiol concentrations to intact control levels, whereas each compound alone had no effect on ovarian weight and stimulated serum estradiol levels by 45% (P < 0.05) and 46% (P < 0.05), respectively. Treatment with EM-800 caused a marked inhibition of uterine and vaginal weight. The present data show the additive inhibitory effects of DHEA and EM-800 on the development of DMBA-induced mammary carcinoma in the rat, thus suggesting the potential benefits of such a combination for the prevention of breast cancer in women while preserving or even increasing bone mass and maintaining a favorable lipid profile.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
BREAST CANCER is the most common cancer and the second most frequent cause of cancer death in women (1). Among all factors, estrogens are recognized to play the predominant role in breast cancer development and growth (2, 3, 4, 5, 6, 7).

As the first step in the action of estrogens in target tissues is activation of the estrogen receptor (8, 9), a logical approach for the prevention of breast cancer is the use of antiestrogens or compounds that block the interaction of estrogens with their specific receptor. This approach is supported by a large series of experimental animal studies (10, 11, 12, 13, 14). Moreover, clinical trials are in progress to evaluate tamoxifen as a chemopreventive agent in women (15, 16).

Dehydroepiandrosterone (DHEA), a sex steroid precursor secreted by the human adrenal cortex, is transformed in peripheral target intracrine tissues into active androgens and/or estrogens (17, 18, 19). Although the physiological role of DHEA remains to be defined, a growing body of evidence suggests an inverse relationship between an alteration in the serum levels or excretion of this steroid or its metabolites and a number of problems associated with aging, including breast cancer and bladder cancer (20, 21, 22), and a series of conditions, such as obesity, autoimmune disease, fatigue, loss of muscle mass, diabetes, poor immune response, and reduced longevity (23, 24, 25, 26, 27, 28). In addition, long term administration of DHEA has been observed to protect against some cancers in animal models of tumorigenesis, including skin, liver, lung, colon, and mammary carcinoma (29, 30, 31, 32, 33, 34).

Dimethylbenz(A)anthracene (DMBA)-induced mammary carcinoma in the rat is a commonly used model for studies of the prevention and treatment of breast cancer. As antiestrogens (10, 11, 12, 13, 14) as well as DHEA (34) can independently inhibit the development of DMBA-induced mammary carcinoma, we have studied the potential benefits of combining the new antiestrogen EM-800 and DHEA on the development of mammary carcinoma induced by DMBA in the rat. As the maintenance of bone density and the lipid profile are main concerns at menopause and during antiestrogen therapy, we have also investigated the effects of such combination on bone mineral metabolism and the serum lipid profile.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Female Sprague-Dawley rats [Crl:CD(SD)Br] were obtained at 44–46 days of age from Charles River Canada (St. Constant, Canada) and housed two per cage in a light (12 h of light/day; lights on at 0715 h)- and temperature (22 ± 2 C)-controlled environment. Animals received Purina rodent chow (Ralston-Purina, St. Louis, MO) and tap water ad libitum. The animal studies were conducted in a Canadian Council on Animal Care-approved facility in agreement with the Canadian Council on Animal Care Guide for Care and Use of Experimental Animals.

Induction of mammary tumors by DMBA
Mammary carcinomas were induced by a single intragastric administration of 20 mg DMBA (Sigma Chemical Co., St. Louis, MO) in 1 ml corn oil at 50–52 days of age. Two months later, tumor measurement was performed biweekly. The two largest perpendicular diameters of each tumor were recorded with calipers to estimate tumor size as previously described (7). Tumor site, size, and number were recorded.

Treatment
The animals were randomly divided into groups, each containing 20 rats, with the exception of 40 animals in the control group. The animals were treated for 282 days with the following: 1) control vehicles, for both DHEA and EM-800; 2) EM-800 [(+)-7-pivaloyloxy-3-(4'-pivaloyloxyphenyl)-4-methyl-2-(4''-(2`''-piperidinoethoxy)phenyl)-2H-benzopyran; Fig. 1Go; 75 µg, orally, once daily] in 0.5 ml of a 4% ethanol, 4% polyethylene glycol-600, 1% gelatin, and 0.9% NaCl suspension; 3) DHEA (10 mg, percutaneously, once daily) in 0.5 ml 50% ethanol and 50% propylene glycol; and 4) both EM-800 and DHEA. Treatment was initiated 3 days before the oral administration of DMBA. EM-800 was synthesized in the Medicinal Chemistry Division of our laboratory, and DHEA was purchased from Steraloids (Wilton, NH).



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  		Figure 1. Structure of EM-800.

 
Many of the control animals and some of EM-800- or DHEA-treated animals were killed by cervical dislocation under isoflurane-induced anesthesia 6 months after DMBA administration because their tumors grew too large. The tumor size and number in these rats at death together with those measured at later time intervals from the surviving animals were used for the later analysis of the incidence of tumors, average tumor number per tumor-bearing rat, and average tumor size per tumor-bearing animal. The remaining animals (9 rats from the control group and 13–19 rats from each other group) continued to receive treatment for another 3-month period to determine the long term preventive potency of DHEA and EM-800 alone or in combination. Rats were killed 279 days after DMBA administration. The uteri, vaginas, and ovaries were immediately removed, freed from connective and adipose tissue, and weighed.

Sample collection and processing
Twenty-four-hour urinary samples were collected at the end of the experiment from the first nine rats of each group after transfer in metabolic cages (Allentown Caging Equipment Co., Allentown, NJ). Two urinary samples were collected and analyzed on different days for each animal to minimize the influence of daily variation. Therefore, each value shown represents the mean of the two measurements performed on 2 different days. Toluene (0.5 ml) was added to the urine-collecting tubes to prevent urine evaporation and bacterial growth, and urinary volume was recorded. Trunk blood was collected at death and was allowed to clot at 4 C overnight before centrifugation at 3000 rpm for 30 min. Serum samples for steroid, LH, and PRL assays were stored at -80 C until assayed.

Analysis of urine and serum biochemical parameters
Fresh samples were used for the assay of urinary creatinine, calcium, and phosphorus as well as serum total alkaline phosphatase (tALP) activity, cholesterol, and triglycerides. These biochemical parameters were measured automatically with a Monarch 2000 Chemistry System (Instrumentation Laboratory Co., Lexington, MA) under good laboratory practice conditions. Urinary hydroxyproline was measured as previously described (35).

Bone mass measurements
Rats were anesthetized with an ip injection of ketamine hydrochloride and diazepam at doses of 50 and 4 mg/kg BW, respectively. The whole skeleton and the right femur were scanned using dual energy x-ray absorptiometry (QDR 2000–7.10C, Hologic, Waltham, MA) equipped with regional high resolution software. The scan field sizes were 28.110 x 17.805 and 5.0 x 1.902 cm, the resolutions were 0.1511 x 0.0761 and 0.0254 x 0.0127 cm, and the scan speeds were 0.3608 and 0.0956 mm/sec for total skeleton and femur, respectively. Both bone mineral content and bone mineral density (BMD) of total skeleton, lumbar spine, and femur were measured on the scan images of total skeleton and femur.

RIAs
Serum steroid concentrations were measured by RIAs after methanol and diethyl ether extraction and chromatography on LH-20 columns as described in detail previously (36). EM-800 does not interfere in the steroid assays used. All samples were chromatographed and radioimmunoassayed simultaneously.

Serum LH and PRL were measured by double antibody RIAs using rat hormones (LH I-6 and PRL I-5 for iodination, rat LH RP-2 and PRL RP-3 as standards), and rabbit antirat LH S-8 and antirat PRL S-8 antisera, generously supplied by the National Pituitary Program (Baltimore, MD).

Histology
Mammary gland was carefully excised, dissected free from the epidermal layer, and immediately immersed in a solution of 10% buffered formalin for 48 h. After fixation, the mammary gland tissue was routinely processed in a tissue processor and embedded in paraffin as previously described (37). Sections of 5–6 µm were cut and stained with hematoxylin-eosin. Examination of the tissue slides was performed by light microscopy.

Statistical analyses
Statistical significance was measured according to the multiple range test of Duncan-Kramer (38). Analysis of the incidence of development of mammary tumors was performed using the Fisher’s exact test (39). The data are presented as the mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effect on the development of DMBA-induced mammary carcinoma
As illustrated in Fig. 2Go, 95% of control animals developed palpable mammary tumors by 279 days after DMBA administration. Treatment with DHEA or EM-800 partially prevented the development of DMBA-induced mammary carcinoma, and the incidence was thus reduced to 57% (P < 0.01) and 38% (P < 0.01), respectively. Interestingly, combination of the two compounds led to a significantly higher inhibitory effect than those achieved by each compound alone (P < 0.01 vs. DHEA or EM-800 alone). In fact, the only two tumors that developed in the group of animals treated with both compounds disappeared before the end of experiment.



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  		Figure 2. Effect of treatment with DHEA (10 mg, percutaneously, once daily) or EM-800 (75 µg, orally, once daily), alone or in combination for 9 months, on the incidence of DMBA-induced mammary carcinoma in the rat throughout the 279-day observation period. Data are expressed as percentage of the total number of animals in each group.

 
Treatment with DHEA or EM-800 decreased average tumor number per tumor-bearing animal from 4.7 ± 0.5 tumors in control animals to 3.4 ± 0.7 (P = NS) and 1.4 ± 0.3 (P < 0.01) tumors/animal, respectively, whereas no tumor was found at the end of the experiment in the animals who received both drugs (P < 0.01 vs. the three other groups; Fig. 3AGo). One of the two tumors that later disappeared was present from days 79–201 after DMBA administration, whereas the other tumor was palpable from days 176–257. It can be seen in Fig. 3BGo that DHEA or EM-800 alone decreased the average tumor area per tumor-bearing animal from 12.8 ± 1.3 cm2 at the end of the experiment to 10.2 ± 2.1 (P = NS) and 7.7 ± 1.8 (P = NS) cm2, respectively, whereas the combination treatment resulted in a zero value (P < 0.01 vs. the three other groups). The two tumors that developed in the group of animals treated with both DHEA and EM-800 did not grow larger than 1 cm2. It should be mentioned that the real values of average tumor area as well as the average tumor number per tumor-bearing animal in the control group should be higher than the values presented in Fig. 3Go, as many rats had to be killed before the end of the experiment because of the excessive size of their tumors. The values measured at the time of death were thus included as such in the calculations made at later time intervals to minimize a bias in the control group values, which, in any case, remained significantly above those in the other groups.



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  		Figure 3. Effect of treatment with DHEA (10 mg, percutaneously, once daily) or EM-800 (75 µg, orally, once daily) alone or in combination for 9 months on average tumor number per tumor-bearing animal (A) and on average tumor size per tumor-bearing rat (B) throughout the 279-day observation period. Data are expressed as the mean ± SEM.

 
Effect on bone
Long term percutaneous administration of DHEA to female rats induced 6.9% (P < 0.01), 10.6% (P < 0.05), and 8.2% (P < 0.01) increases in BMD of total skeleton, lumbar spine, and femur, respectively (Table 1Go). On the other hand, no significant change was found in the animals treated with EM-800. Furthermore, when both compounds were administered simultaneously, the values obtained were comparable to those achieved with DHEA alone.


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  		Table 1. Effect of treatment with DHEA (10 mg, percutaneously, once daily) or EM-800 (75 µg, orally, once daily) alone or in combination for 9 months on bone mineral density (BMD) of femur, lumbar spine, and total skeleton in the female rat

 
Treatment with DHEA increased serum tALP activity by 74% (P < 0.05), but had no effect on daily urinary calcium and phosphorus excretion or on the urinary ratio of hydroxyproline to creatinine (Table 2Go). On the other hand, treatment with EM-800 decreased the urinary hydroxyproline to creatinine ratio by 48% (P < 0.01), but had no statistically significant influence on daily urinary calcium or phosphorus excretion and serum tALP activity. The combination of DHEA and EM-800 led to an increase in serum tALP activity (P < 0.01) similar to that achieved with DHEA alone and reduced the urinary hydroxyproline to creatinine ratio by 69%, a value significantly (P < 0.01) lower than that achieved with EM-800 alone. In addition, the combination of the two drugs significantly reduced daily urinary calcium and phosphorus excretion by 84% (P < 0.01) and 56% (P < 0.01), respectively, whereas no significant change was observed with either drug alone (Table 2Go).


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  		Table 2. Effect of treatment with DHEA (10 mg, percutaneously, once daily) or EM-800 (75 µg, orally, once daily) alone or in combination for 9 months on parameters of bone metabolism in the rat: daily urinary calcium and phosphorus excretion, urinary hydroxyproline to creatinine ratio (HP/Cr), and serum total alkaline phosphotase activity (tALP)

 
Effect on serum lipid levels
Long term treatment with EM-800 lowered serum triglyceride and cholesterol levels by 72% (P < 0.01) and 45% (P < 0.01), respectively, whereas long term administration of DHEA decreased serum triglycerides levels by 60% (P < 0.01); serum cholesterol levels were unaffected. Moreover, 42% (P < 0.01) and 52% (P < 0.01) decreases in serum triglyceride and cholesterol concentrations were measured in the animals treated with both EM-800 and DHEA (Fig. 4Go).



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  		Figure 4. Effect of treatment with DHEA (10 mg, percutaneously, once daily) or EM-800 (75 µg, orally, once daily) alone or in combination for 9 months on serum triglyceride (A) and cholesterol (B) levels in the rat. Data are expressed as the mean ± SEM. **, P < 0.01, experimental vs. respective control.

 
Histology of the mammary gland
The histological pattern of the mammary gland in control animals is characteristic of that seen in female rats, aged 11–12 months or older: namely, mild to moderate lobular hyperplasia accompanied by an apparent increase in the secretory activity and a moderate to marked duct dilatation (duct ectasia; Fig. 5Go, A1 and A2). Individual acini were lined by epithelial cells mainly filled with clear and, to a lesser degree, eosinophilic vacuoles in their cytoplasm (Fig. 6AGo). We also observed a marked dilatation of ducts resulting from the accumulation of secretory material, cell debris, and foamy macrophages into their lumen (duct ectasia).



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  		Figure 5. Mammary gland histology in rats treated with vehicle (A1–A2), DHEA (10 mg, percutaneously, once daily; B1–B2), EM-800 (75 µg, orally, once daily; C1-C2), or DHEA (10 mg, percutaneously, once daily; D1–D2) plus EM-800 (75 µg, orally, once daily). In intact animals, lobular structures (L) were numerous, and dilatation of mammary ducts (d) was seen (DE, duct ectasia). Note the atrophic mammary gland observed after EM-800 administration to intact animals (C1–C2) and the moderate lobular hyperplasia (L) seen after addition of DHEA to EM-800. Hematoxylin-eosin stain was used; magnification, x80 (A1, B1, C1, and D1) and x200 (A2, B2, C2, and D2).

 


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  		Figure 6. Mammary gland histology in rats treated with vehicle (A), DHEA (10 mg, percutaneously, once daily; B), EM-800 (75 µg, orally, once daily; C), or DHEA (10 mg, percutaneously, once daily; D) plus EM-800 (75 µg, orally, once daily). This figure is a larger magnification of Fig. 5Go, demonstrating the acinar cell morphology. Note the atrophic acinal cells (ac) in rats treated with EM-800 (C). An accumulation of numerous, mainly eosinophilic, cytoplasmic vacuoles (ev) in the acinar cells was observed after the addition of DHEA to EM-800 (D). Hematoxylin-eosin stain was used; magnification, x800.

 
After DHEA administration, there was a decrease in the size of the lobuloalveolar structures, which consisted of hypertropic acinar epithelial cells mainly filled with eosinophilic and, to a lesser degree, clear secretory vacuoles (Fig. 6BGo). Mammary ducts were only focally, mildly dilated, and no duct ectasia was present (Figs. 5Go, B1 and B2).

On the other hand, treatment of intact animals with EM-800 resulted in a marked atrophy of the mammary gland (Figs. 5Go, C1 and C2). The EM-800-induced pattern was characterized by a decreased size of the lobular structures, which consisted of small atrophic alveoli, lined by atrophic and low cuboidal epithelial cells. The acinar epithelial cells were apparently inactive, with a diminished quantity of cytoplasm (Fig. 6CGo).

Interestingly, after simultaneous long term administration of DHEA and EM-800, a significant increase in the amount of lobuloalveolar tissue of the mammary gland was noted. The moderate lobular hyperplasia observed was characterized by an increased size and number of the lobular structures (Fig. 5Go, D1 and D2). The lobuloalveolar units consisted of groups of alveoli lined by hypertropic epithelial cells with a highly eosinophilic cytoplasm filled mainly with eosinophilic secretory vacuoles (Fig. 6DGo).

Effect on serum steroid levels
As shown in Fig. 7AGo, daily treatment with DHEA significantly increased serum DHEA levels, whereas treatment with EM-800 had no effect on this parameter. The addition of EM-800 to DHEA did not significantly affect the elevated levels of serum DHEA caused by DHEA treatment.



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  		Figure 7. Effect of treatment with DHEA (10 mg, percutaneously, once daily) or EM-800 (75 µg, orally, once daily) alone or in combination for 9 months on serum DHEA (A), androstenedione (4-dione) (B), androst-5-ene-3ß, 17ß-diol (5-diol) (C), testosterone (D), dihydrotestosterone (E), and estradiol (F) levels in the rat. Data are expressed as the mean ± SEM. **, P < 0.01, experimental vs. respective control.

 
In control animals, serum 4-dione (Fig. 7BGo), testosterone (Fig. 7DGo), and dihydrotestosterone (Fig. 7EGo) levels were not detectable, whereas serum 5-diol (Fig. 7CGo) was measured at 2.24 ± 0.38 nmol/L. Daily administration of DHEA increased the serum concentrations of all of these steroids, whereas treatment with EM-800 had no effect when administered alone or with DHEA.

Both DHEA and EM-800 moderately, but significantly, increased serum estradiol levels (P < 0.05), respectively, but the combination of DHEA and EM-800 slightly lowered serum estradiol levels to a value not significantly different from that measured in intact controls (Fig. 7FGo).

Effect on serum LH and PRL levels
DHEA treatment decreased serum LH levels (P < 0.01), whereas treatment with EM-800 did not affect serum LH levels when given alone or in the presence of DHEA (Fig. 8AGo). Long term treatment with EM-800 markedly lowered serum PRL levels (P < 0.01); this effect of EM-800 was not affected by the addition of DHEA (Fig. 8BGo).



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  		Figure 8. Effect of treatment with DHEA (10 mg, percutaneously, once daily) or EM-800 (75 µg, orally, once daily) alone or in combination for 9 months on serum LH (A) and PRL (B) levels in the rat. Data are expressed as the mean ± SEM. **, P < 0.01, experimental vs. respective control.

 
Effect on uterine, vaginal, and ovarian weight
As shown in Table 3Go, long term treatment with DHEA or EM-800 alone did not affect ovarian weight, whereas the combination of both compounds lowered ovarian weight by 24% (P < 0.01). Although DHEA alone did not change uterine weight, EM-800 markedly decreased uterine weight (P < 0.01), and the combination of both compounds resulted in a somewhat lower inhibition of uterine weight than that achieved with EM-800 used alone (P < 0.01 vs. control or EM-800 alone). Although DHEA moderately stimulated vaginal weight (P < 0.05), EM-800 markedly inhibited the value of this parameter (P < 0.01). Similarly, the inhibitory effect of EM-800 on vaginal weight was neutralized by the addition of DHEA to EM-800. Only treatment with EM-800 significantly decreased body weight (P < 0.01); the inhibitory effect of EM-800 on body weight was prevented by simultaneous treatment with DHEA.


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  		Table 3. Effect of treatment with DHEA (10 mg, percutaneously, once daily) or EM-800 (75 µg, orally, once daily) alone or in combination for 9 months on body, uterine, vaginal, and ovarian weights in the rat

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Estrogens are well known to stimulate the proliferation of breast epithelial cells, and cell proliferation itself is thought to increase the risk of cancer by accumulating random genetic errors that may result in neoplasia (40). Based on this concept, antiestrogens have been introduced to prevent breast cancer with the objective of reducing the rate of cell division stimulated by estrogens.

The loss of ovarian cyclicity found in female Sprague-Dawley rats after 10 months of age is accompanied by increased serum estrogen and PRL levels and decreased serum androgen and progesterone concentrations (41, 42, 43, 44, 45). These hormonal changes that spontaneously occur in aging female rats are associated with multifocal proliferation and increased secretory activity of the acinar/alveolar tissue as well as mammary gland duct dilatation and formation of cysts (42, 46). Hyperplastic and neoplastic changes in the rat mammary gland are often accompanied by increased levels of estrogens and PRL (47). EM-800 is a potent nonsteroidal antiestrogen (48, 49, 50). The present study shows that treatment with EM-800 induces atrophy of the mammary gland, characterized by a decrease in the size and number of the lobular structures and no evidence of secretory activity. Such data indicate the potent antiestrogenic activity of EM-800 in the mammary gland.

The present data show that treatment with DHEA leads to a marked elevation in serum DHEA and 5-diol, whereas serum 4-dione, testosterone, dihydrotestosterone, and estradiol levels are moderately increased, thus confirming the biotransformation of this precursor steroid. However, the stimulatory effect of DHEA on serum androgens, such as testosterone and dihydrotestosterone, is of greater amplitude than the effect on serum estrogens, namely estrone (serum estrone levels were not detectable, namely <172 pmol/liter; data not shown) and estradiol levels, thus suggesting that DHEA is predominantly transformed into androgens in these animals. This observation is in agreement with the data obtained in women where the formation of androgens from DHEA was a more important pathway than the conversion of DHEA into estrogens (51, 52, 53).

After DHEA administration to intact animals, the mammary gland was composed of lobular structures lined by epithelial cells filled with many clear cytoplasmic, secretory vacuoles. Interestingly, we have recently shown that DHEA exerts a predominant androgenic effect on the mammary gland of ovariectomized female rats, including hypertrophy and enhanced secretory activity of the alveolar epithelial cells as well as promotion of lobuloalveolar growth; this effect is blocked by the antiandrogen flutamide (Sourla, A., et al., unpublished data). It is also noteworthy that the effect of DHEA, namely a lobuloalveolar type of development of the mammary gland, is similar to that seen in male rats (42), in which the histopathological pattern is different from that observed in both young mature and aged female rats (41).

With the knowledge of the above-described potent antiestrogenic activity of EM-800 resulting in mammary gland atrophy and the predominant androgenic effect of DHEA on the mammary gland, the histomorphological changes seen in animals treated with the combination of EM-800 and DHEA are best explained by an unopposed androgenic action of DHEA.

It has been observed that androgens exert a direct antiproliferative activity on the growth of ZR-75–1 human breast cancer cells in vitro and that such an inhibitory effect of androgens is additive to that of an antiestrogen (6, 54). Similar inhibitory effects have been observed in vivo on ZR-75–1 xenographs in nude mice (12). Androgens have also been shown to inhibit the growth of DMBA-induced mammary carcinoma in the rat; this inhibition is reversed by the simultaneous administration of the pure antiandrogen flutamide (55). Taken together, the present data indicate the involvement of the androgen receptor in the chemopreventive action of DHEA. As antiestrogens and DHEA exert chemopreventive effects on breast cancer via different mechanisms, it is reasonable to expect that the combination of EM-800 and DHEA exerts more potent inhibitory effects than each compound used alone on the development of DMBA-induced rat mammary carcinoma, as well illustrated by the present data. PRL is a potent stimulus of the growth and development of DMBA-induced mammary carcinoma in the rat (7, 56).

It is of interest that the combination of DHEA and EM-800 maintained the stimulatory effect of DHEA on bone formation and potentiated the inhibitory effect of EM-800 alone on bone turnover and resorption, as demonstrated by the further decreases in urinary hydroxyproline and calcium excretion. The limitations of BMD measurements are well known. As an example, BMD measurements showed no change in rats treated with the antiestrogen ICI 182780 (57), whereas inhibitory changes were seen by histomorphometry (58). Similar differences were reported with tamoxifen (59, 60). However, our recent findings of a stimulatory effect of DHEA on BMD in postmenopausal women are in agreement with the present findings (61).

Estrogens are known to lower serum cholesterol, but to increase or have no effect on serum triglyceride levels (62, 63, 64, 65, 66, 67, 68). The present data show that EM-800 possesses both hypocholesterolemic and hypotriglyceridemic effects in the rat, thus showing its unique action on the serum lipid profile, which is apparently different from those of other antiestrogens, such as tamoxifen (64, 65, 69, 70), droloxifene (65), and raloxifene (63). The combination of DHEA and EM-800 preserved the hypocholesterolemic and hypotriglyceridemic effects of EM-800, thus suggesting that such a combination could exert beneficial effects on serum lipids. It should be mentioned that the serum lipid profile is markedly different between rats and humans. However, as an estrogen receptor-mediated mechanism is involved in the hypocholesterolemic effect of estrogens as well as antiestrogens (71), the rat remains a useful model to study the cholesterol-lowering effect of estrogens and antiestrogens in humans. However, the present findings in the rat remain to be demonstrated in the human (61, 72). As no untreated controls were studied in this experiment, it should be mentioned that control rats were tumor bearing; there is some possibility that the observed changes could be due in part to a reduction in tumor burden rather than to the specificity of treatment.

In brief, the above-described data clearly demonstrate the additive chemopreventive effects of the novel antiestrogen EM-800 and DHEA on the development of mammary carcinoma induced by DMBA as well as the protective effects of such a combination on bone mass and serum lipids; such data suggest additional beneficial effects of such a combination for the prevention of osteoporosis while improving the lipid profile.


   Acknowledgments
 
We express thanks to Dr. Jim Gourdon, Mr. Roger Lachance, Mr. Simon Caron, Mrs. Louise Mailloux, and Mrs. Diane Bastien for their skillful technical assistance.


   Footnotes
 
1 This work was supported by Endorecherche. Back

Received April 16, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Parker SL, Tong T, Bolden S, Wingo PA 1997 Cancer statistics 1997. CA Cancer J Clin 47:5–27[Medline]
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