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Medical Research Council (MCR) Group in Molecular Endocrinology, CHUL (Centre Hospitalier de l’ Université Laval) Research Center and Laval University, Québec, G1V 4G2, Canada
Address all correspondence and requests for reprints to: Professor Fernand Labrie, Medical Research Council (MRC) Group in Molecular Endocrinology, CHUL (Centre Hospitalier de l’ Université Laval) Research Center, 2705 Laurier Boulevard, Québec, Canada G1V 4G2.
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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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Although mammary gland histology and structure do not differ significantly in young male and female rats (16), the first estrous cycle in female Sprague-Dawley rats results in a rapid growth and differentiation of the mammary gland, a change that can be prevented by ovariectomy (17). In fact, the rat mammary gland is a highly hormone-sensitive tissue (18, 19). In addition, it has been demonstrated that not only ovarian hormones but also mammotrophic hormones of anterior pituitary and of adrenal origin as well as local factors play an important role in the modulation of proliferation and differentiation of the mammary tissue in vivo and in vitro (14, 20, 21, 22).
The rat mammary gland has been widely used as model of hormone-sensitive breast cancer in women (23, 24, 25). On the other hand, androgens have been successfully used for the treatment of breast cancer in women, achieving an objective response comparable to other hormonal therapies (26, 27, 28, 29). In addition, it has been shown that androgens such as dromostanolone propionate and testosterone and dehydroepiandrosterone (DHEA), a precursor of androgens (30, 31), exert a potent inhibitory effect on the development of DMBA-induced mammary carcinoma in the rat (23, 32, 33, 34).
Although DHEA and its sulfate DHEA-S of adrenal origin represent a major source of active sex steroids through their intracrine conversion into potent androgens and estrogens in peripheral tissues (31, 35), their physiological role remains largely unknown. On the other hand, despite the fact that a series of studies have shown the chemopreventive effect of DHEA on the development of rat mammary cancer (23, 32, 36), little is known about the effect of long-term administration of DHEA on mammary gland physiology and structure.
We have used the ovariectomized (OVX) female Sprague-Dawley rat model to investigate the potential effect of DHEA and its active metabolites on the mammary gland histomorphology and structure in adult virgin female rats. We have also compared the effect of DHEA with that of estradiol, medroxyprogesterone, as well as the nonaromatizable androgen dihydrotestosterone (DHT), and we have also used the pure antiandrogen flutamide (FLU) and the pure antiestrogen EM-800 to assess the specific androgenic and/or estrogenic actions of DHEA in the rat mammary gland.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Sixty-four rats were randomly distributed into eight groups of eight animals each as follows: 1) intact control; 2) OVX control; 3) OVX + medroxyprogesterone acetate (MPA); 4) OVX + 17ß-estradiol (E2); 5) OVX + DHT; 6) OVX + DHEA; 7) OVX + DHEA + FLU; 8) OVX + DHEA + EM-800. On the first day of the experiment, the animals of the appropriate groups underwent bilateral OVX under isoflurane-induced anesthesia and one SILASTIC brand silicon implant (Dow Corning, Midland, MI) of E2 or DHT was inserted sc in the dorsal area of each animal of the indicated groups. Implants had the following sizes and concentrations: E2: [cholesterol (1:250, wt:wt), 0.5 cm (length), 0.125 inch (outer diameter), and 0.062 inch (inner diameter)]; DHT: [cholesterol (30:100, wt:wt), 2.5 cm (length), 0.125 inch (outer diameter) and 0.062 inch (inner diameter)]. During the course of the experiment, the implants were replaced every 4–6 weeks. MPA was released from poly(lactide-co-glycolide) microspheres (30 mg) injected sc every 3 months in 2% carboxymethylcellulose, 1% Tween-80 and water. Treatment with the antiandrogen FLU (4'-nitro-3'-trifluoremethylisobutyranilide) (7.5 mg, injected sc twice daily), the antiestrogen EM-800 ((+)-7-pivaloyloxy-3-(4'-pivaloyloxyphenyl)-4-methyl-2-(4''-(2`''-piperidinoethoxy)phenyl)-2H-benzopyran) (250 µg, per os, once daily) (37, 38, 39), and DHEA (30 mg, percutaneous application, twice daily on an approximately 3 cm x 3 cm shaved area of dorsal skin) was initiated on the morning of day 1 of the experiment (40). FLU and EM-800 were administered in 4% ethanol, 4% polyethylene glycol-600, 1% gelatin and 0.9% NaCl, and DHEA was administered in 50% ethanol-50% propylene glycol.
Histology
After 12 months of treatment, the animals were killed by
exsanguination from the abdominal aorta under isoflurane anesthesia.
The mammary glands were then removed and immediately immersed in a
solution of 10% buffered formalin for 48 h. After fixation,
mammary gland tissue was processed in a tissue processor and embedded
in paraffin blocks. Sections of 5-µm thickness were prepared and
stained with hematoxylin-eosin. Histopathologic examination of tissue
slides was performed by light microscopy.
Whole-mount preparation
Mammary glands were carefully excised, dissected free from the
epidermal layer, stretched onto slides, and immersed in 25% glacial
acetic acid in EtOH for 16 h. After fixation, slides were washed
in 70% EtOH and distilled water and stained with Carmine Alum
overnight. Slides were then dehydrated in increasing concentrations of
EtOH (70–100%) in xylene. Examination was then performed under a
stereoscope and a light microscope after mounting with Permount glue
(Fisher Scientific, Ltd., Nepean, Ontario, Canada) (41).
Quantitative analysis
The total as well as the parenchymal surface areas of the
abdominal mammary gland of each animal were measured by tracing the
gland with a stylus in the whole mount preparation and projection on a
digitizer tablet of a Bioquant Morphometry System (Bioquant Meg IV
System, RLM, Biometrics Corp., Nashville, TN) and a SummaSketch
(Summagraphics, now owned by Calcomp Technology, Inc., Anaheim, CA)
digitalizing tablet in conjunction with a Leitz Aristoplan (Leica
Microsystems Canada, Inc., Montreal, Québec, Canada) microscope
as previously described (42). In addition, the number of ducts and
lobuloalveolar structures present per/mm2 of total surface
area of the mammary gland was measured using the same Bioquant
morphometry system. The 5-µm sections obtained at different levels of
the mammary gland were analyzed from each of the eight animals per
group.
Statistical analysis
Data are expressed as the means ± SEM of data
obtained from eight animals per group. Statistical significance was
determined according to the multiple-range test of Duncan-Kramer
(43).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). In this and all
other figures, the results shown are representative of the pattern seen
in all animals of each group. The alveoli consist of foamy acinar cells
mainly filled with clear secretory vacuoles (Fig. 2A). In addition, cystic dilatation of
both the mammary ducts and alveolar lumen by eosinophilic secretory
material is observed (Fig. 2A). In whole mount preparations, the
tubuloalveolar pattern of development of the mammary gland is
characterized by a marked ductal branching with many alveolar buds
(ABs), the latter being organized in well developed, hypertrophic
lobules (Fig. 3A).
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); it contains only small atrophic ducts lined by a
flattened atrophic epithelium (Fig. 2B). No acinar or lobular structure
is seen. In the whole mount preparation, the mammary gland consists
only of a few primary, secondary, and tertiary ducts with a few lateral
buds, whereas no ABs or lobular structures can be seen (Figs. 3B and 4A).
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). In the whole mount preparation, a more
developed duct system compared with OVX controls is observed. These
MPA-induced changes are characterized by an increased number of
secondary and tertiary ducts with the predominance of lateral buds,
terminal end buds (TEBs), and terminal ducts (TDs). Occasionally, small
ABs can also be seen (Figs. 3C and 4B).
A partial reversal of the marked atrophy of the mammary gland observed
12 months after ovariectomy was seen after estradiol treatment of OVX
animals (Fig. 1D). The estrogenic effect is characterized by the
induction of a tubuloalveolar type of development. A well developed
duct system with clusters of alveoli forming a few small lobular
structures is seen. The ductal as well as the alveolar epithelium
consist of low, cuboidal epithelial cells, without evidence of
increased secretory activity (Fig. 2D). In the whole mount preparation,
estradiol administration is seen to induce mainly the development of
the duct system (Fig. 3D). Thus, a significant increase in ductal
length as well as ductal thickness and lateral branching is observed,
compared with OVX controls, as well as to animals treated with MPA. An
increase in the number of tertiary ducts is also seen, with many
lateral and terminal end buds, the latter giving rise to ABs that are
organized into small primitive lobules (Figs. 3D and 4C).
DHT treatment, on the other hand, induces a marked increase in the
number of lateral buds, TEBs, TDs, and ABs (Fig. 1E). As well
illustrated in the whole mount preparation, this effect of DHT is more
pronounced than that observed after estradiol administration (Fig. 1D).
In addition, the presence of small lobular structures is also observed
(Figs. 3E and 4D). Histologically, the mammary gland is composed of an
increased number of small lobuloalveolar units and the
ovariectomy-induced atrophy is thus partially reversed at the dose
used. In addition, the alveoli are lined by hypertrophic eosinophilic
acinar cells containing secretory vacuoles (Fig. 1E).
As illustrated in Fig. 1F, a complete reversal of the mammary gland
atrophy caused by castration is seen after DHEA administration to OVX
animals. A profuse lobular growth is observed, the mammary gland being
composed of a well developed duct system and a large number of lobular
structures exhibiting a typical lobuloalveolar type of development. In
addition, a mild to moderate lobular hyperplasia is observed after DHEA
treatment with an increased number and size of lobular structures.
These numerous lobular structures are lined by hypertrophic acinar
cells filled with mainly eosinophilic and clear secretory vacuoles,
displacing laterally or basally the small darkly stained nuclei.
Occasionally, the alveolar lumen is filled with secretory material and
a mild dilatation of ducts can be seen (Fig. 2C). In whole mount
preparations, an increase in lateral branching, and mainly in the
number and size of the ABs and lobules is observed, with a consequent
significant increase in the amount of lobuloalveolar tissue (Figs. 3E and 4D).
The addition of FLU to DHEA treatment resulted in an almost complete
prevention of the DHEA-induced histological changes of the mammary
gland (Fig. 1G). The mammary gland was then mainly composed of the duct
system, with only occasional remaining small lobules
consisting of alveoli lined by low cuboidal epithelial cells. The
presence of brownish-yellowish material is also seen in the cytoplasm
of both acinar cells and cells lining the ducts, thus giving a foamy
appearance to the epithelial cells (Fig. 2D). In whole mount
preparations, the mammary gland consist of primary, secondary, and
tertiary ducts and TEBs with a marked decrease in lateral branching as
well as in the number of ABs compared with DHEA alone. No formation of
lobular structures could be seen (Figs. 3G and 4F). It is also of
interest to note that although FLU prevented the changes induced by
DHEA treatment, the mammary gland did not reach the severe atrophy seen
in control OVX animals 12 months after castration.
On the other hand, following combined treatment with DHEA and EM-800,
no significant histological changes were observed compared with those
seen in OVX animals treated with DHEA alone. The mammary gland was
composed of a well developed duct system, with a large number of well
developed lobular structures presenting a lobuloalveolar type of
development (Fig. 1H). In addition, a mild to moderate lobular
hyperplasia was observed, this pattern being characterized by an
increased number and size of lobular structures, as seen in OVX animals
treated with DHEA alone. A marked hypertrophy and eosinophilia of the
epithelial cells lining the alveoli is also noted, this being
accompanied by a significant accumulation of mainly eosinophilic and
clear secretory vacuoles in the cytoplasm (Fig. 2E). In the whole mount
preparations, the structure of the mammary gland is characteristic of a
lobuloalveolar type of development, analogous to that seen in animals
treated with DHEA alone; a significant increase in lateral branching,
with the predominant presence of hypertrophic lobuloalveolar units are
seen (Fig. 3H, 4G).
Quantitative analysis
Ovariectomy resulted in a dramatic decrease in the total as well
as parenchymal surface areas of the mammary gland s compared with
intact controls (Figs. 5 and 6). After
treatment with estradiol, significant increases of the total and
parenchymal surface areas of the mammary gland were observed from
55 ± 3.5 mm2 to 450 ± 48.5 mm2
(P < 0.01) and from 5.5 ± 2.1 to 196 ±
46.1 mm2 (P < 0.01), respectively. After
MPA administration, increases of the total and parenchymal surface
areas of the mammary gland to 75 ± 10.4 mm2 and
28.5 ± 13 mm2 were observed, respectively
(P < 0.05). On the other hand, at the dose used, DHT
treatment resulted in a more important stimulation of the
above-indicated parameters that increased to 550 ± 76.5
mm2 (P < 0.01) and to 255 ± 32.5
mm2 (P < 0.01), respectively (Figs. 5 and 6). In the same figures, it can be seen that DHEA treatment induced a
marked increase in both the total and parenchymal surface areas to
1680 ± 214 mm2 (P < 0.01) and
1200 ± 125 mm2 (P < 0.01),
respectively.
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). All the
above-described stimulatory effects of DHEA were almost completely
reversed by concomitant treatment with FLU, which returned the total
and parenchymal surface areas to values not significantly different
from those measured in OVX control animals. On the contrary, the
administration of the pure antiestrogen EM-800 in combination with DHEA
had no influence on the effect of DHEA on the parameters measured
(
Figs. 5–7).
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), whereas the number of ducts was markedly decreased from 2.4 ±
0.2/mm2 to 1.0 ± 0.0 mm2
(P < 0.01) after ovariectomy.
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and 9). The effect of DHEA on the number of
lobuloalveolar units was completely abolished by the concomitant
administration of FLU, whereas the addition of EM-800 had no effect to
the action of DHEA (Fig. 8). On the other hand, administration of
E2 resulted in a significant increase of the number of
ducts per mm2 of total surface area to 2.6 ±
0.2/mm2 from 1.0 ± 0.0/mm2 in OVX
controls (P < 0.01) (Fig. 9). Treatment with MPA and
DHT also stimulated ductal growth from 1.0 ± 0.0/mm2
to 1.6 ± 0.2/mm2 (P < 0.05) and
1.8 ± 0.2/mm2 P < 0.05),
respectively, although the effect was inferior to that achieved with
E2 (Fig. 9).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mammary gland development, growth, function, and morphology are well known to be dependent upon the endocrine system. Duct and alveolar tissue are structures responsive to hormonal changes observed during the estrous cycle, pregnancy, lactation, and with aging and diet (6, 13, 42). The mammary gland of virgin female rats consists mainly of a well developed duct system including a large number of TEBs, TDs, ABs, and as a few lobules, this pattern being characteristic of a tubuloalveolar type of development. During pregnancy and lactation when the mammary gland reaches its full development and maturity, a profuse lobular development accompanied by a marked stimulation of secretory activity of alveolar epithelium is observed (15, 42).
The multifocal proliferation and the increased secretion of the acinar/alveolar tissue associated with duct dilatation and formation of cysts, seen in the intact animals aged approximately 16 months, represent spontaneously occurring changes during aging in female rats (44, 45). The loss of regular ovarian cyclicity that characterizes aging, especially after 12 months of age, is accompanied by alterations in the serum levels of various hormones, especially estrogens and progestins. More specifically, it has been shown that at 12–19 months of age, female rats enter into a stage of constant estrous accompanied by increased serum estrogen and PRL levels and decreased progesterone concentrations compared with young cycling animals (44, 46, 47). The above-indicated alterations of the hormonal milieu, and especially the increased serum PRL levels, can be correlated with the morphological alterations of the mammary gland seen in aging female rats. It is also well known that the loss of estrous cycles associated with reduced levels of gonadotropins and increased levels of estrogens and PRL are often accompanied by the development of hyperplastic and neoplastic changes of the rat mammary gland (20).
The majority of the intact control animals in our study, aged approximately 15 months, also showed histomorphological signs typical of a chronic anovulatory state, thus explaining the inappropriate secretory activity of the acinar epithelium as well as duct dilatation-ectasia and lobular hyperplasia in the mammary gland. Whereas ovariectomy resulted in a compete atrophy of the mammary gland, estradiol administration mainly induced an increase in duct proliferation and branching with a much less important stimulation of acino-lobular development. The above-indicated stimulatory effects of estradiol on mammary gland development were also reflected in significant increases in the total and parenchymal surface areas of the gland. These results are in agreement with the known effects of estradiol treatment on the mammary gland of female rats (minimal acinar development, maximal stromal, and ductal cell proliferation) (48). In addition, ductal elongation and branching are events known to be under the control of estradiol starting at time of initiation of mammary gland development (48, 49, 50).
At the dose used, MPA administration had minor effects on the duct system. Although at a much lesser degree than that of estradiol, MPA slightly increased the lateral branching as well as the number of TEBs and TDs. Interestingly, a small number of ABs were also observed after MPA administration. The ABs of MPA-treated OVX animals were composed of epithelial cells that contained secretory vacuoles, whereas in OVX controls, the mammary gland only consisted of a few atrophic ducts lined by atrophic, low cuboidal, and inactive epithelium. The above-described histological changes were also accompanied by significant increases in the number of ducts and lobuloalveolar structures present per mm2 of total surface area of the mammary gland as compared with OVX controls.
It is reported that progestins can stimulate the mammary gland of female rats by increasing PRL release (51, 52, 53, 54). Furthermore, high doses of estradiol have been reported to induce cystic mastopathy associated with increased secretory activity, these effects being potentiated by combination with a progestin (55, 56). It is well demonstrated in both rats (57, 58, 59, 60, 61, 62) and mice (63) that the androgenic activity of MPA is exerted through direct interaction with the androgen receptor. Similarly, the histological MPA-induced changes of the mammary gland possibly represent a direct androgen receptor-mediated effect of MPA on the mammary gland.
DHT administration to OVX animals induced an important increase in lateral ductal branching, as well as in the number of TEBs and TDs. In addition, the presence of numerous alveolar structures and lobular units, showing secretory activity, were also seen. At the doses of DHEA and estradiol used, the above-summarized histological changes of the mammary gland induced by DHT treatment were more pronounced than those achieved after estradiol administration. In addition, a significant increase in the total and parenchymal surface areas of the mammary gland as well as in the number of ducts and lobuloalveolar structures present per mm2 of the total surface area of the gland were observed after DHT treatment. Knowing that DHT cannot be aromatized into estrogens, the present data indicate a direct androgenic action.
DHEA is a sex steroid precursor that is metabolized into active androgens and/or estrogens in peripheral intracrine tissues, depending upon the relative activities and types of steroidogenic enzymes expressed in each tissue and cell (31, 35). The mammary gland is likely to possess all the steroidogenic enzymatic systems necessary for the formation of androgens and estrogens from steroid precursors, such as DHEA (64, 65, 66, 67, 68, 69). The complete reversal of the ovariectomy-induced mammary gland atrophy seen after DHEA treatment was characterized by a marked stimulation of the ductal and mainly the lobular structures. In addition, epithelial cell hypertrophy and a marked stimulation of secretory activity were seen, these effects being accompanied by the accumulation of clear and eosinophilic vacuoles in the cytoplasm of the acinar cells. As mentioned above, the above-indicated histological changes characterizing a rather lobuloalveolar type of development of the mammary gland, are analogous to those seen during pregnancy and lactation (14, 70).
In the OVX female Sprague-Dawley rat, exogenous DHEA represents the only source of sex steroids in peripheral tissues, including the mammary gland. It should also pointed out that DHEA does not possess any significant androgenic or estrogenic activity by itself. Thus, the stimulation of lobuloalveolar growth seen after DHEA treatment in OVX animals results from its intracrine in situ conversion into potent androgens and/or estrogens in the mammary gland (31, 67, 68).
It is also noteworthy that, after DHEA treatment, the increase in total gland surface area was mainly due to an increase in the parenchymal surface area, thus resulting in a parenchymal to stromal ratio greater than that observed in intact animals. Furthermore, the observed increase in parenchymal surface area was mainly associated with an increase in the number of lobuloalveolar structures and to a lesser degree by an increase in the number of ducts present per mm2 of total surface area of the mammary gland. Interestingly, the stimulation of lobuloalveolar growth of the mammary gland was almost completely abolished by the concomitant administration of the pure antiandrogen FLU, thus providing evidence for the predominant androgenic effect of DHEA, through its intracrine conversion to active sex steroids with androgenic activity. The mammary gland of OVX animals treated with the combination of DHEA and FLU, although not reaching the severe atrophy seen in OVX control animals, did not demonstrate lobular development. The mammary gland was, in fact, composed of a few ducts and alveolar units without evidence of secretory activity of the epithelial cells. Van Wanegen et al. (71) and Selye et al. (72) have reported the stimulatory effects of androgens, such as testosterone, on lobuloalveolar development in both the rhesus monkey and rat. The lobuloalveolar type of development of the mammary gland is characterized by the predominance of numerous, contiguous lobular structures composed of acinar epithelial cells with abundant, foamy cytoplasm filled with secretory vacuoles, and it is also seen in adult male Sprague-Dawley rats. Moreover, Cardy (44) has reported that the lobuloalveolar structure of the mammary gland seen in male rats can be altered and assume tubuloalveolar characteristics indistinguishable from those seen in adult female rats, after hormonal manipulation with compounds that increase PRL release. In the same report, it was suggested that progestins as well as androgens could stimulate lobuloalveolar growth.
Nevertheless, although it is reported that androgens can stimulate lobuloalveolar growth, our study demonstrates for the first time the stimulatory androgenic-like effect of DHEA on the mammary gland, which not only resulted in a complete reversal of the ovariectomy-induced atrophic changes of the mammary gland but also led to a profuse lobuloalveolar development. In addition, we have also demonstrated the potent stimulatory effect of DHT, a nonaromatizable androgen on the growth of the rat mammary gland, thus indicating that the above-described effects are mediated through the androgen receptor. Furthermore, in the present study, the absence of a significant increase in serum PRL levels in DHEA-treated animals appears to exclude the possibility of a role of PRL in the major DHEA-induced histological changes. Following the combined administration of DHEA and EM-800 to OVX rats, the same lobuloalveolar pattern of development of the mammary gland was seen as that observed after treatment with DHEA alone, thus practically eliminating the role of estrogens in the action of DHEA. It is also important to mention that EM-800 does not have any effect on the mammary gland histopathology when given to OVX rats, as reported for the mouse by Luo et al. (39). The 250-µg daily dose of EM-800 used in the one shown in a series of preclinical pharmacological and toxicological (our unpublished observations) studies (37, 38, 39, 73) to exert maximal antiestrogenic activity.
It is also noteworthy that lobular development and lobular hyperplastic lesions, such as hyperplastic alveolar nodules, often accompanied by enhanced secretory activity (74) are not considered as preneoplastic lesions in the rat (75). The susceptibility and responsiveness of the mammary gland to various exogenous or endogenous hormonal stimuli is modulated by local factors such as the tissue concentration of specific receptors (76). Androgens, on the other hand, are known to be able to alter the concentration of other receptors in mammary tissue, such as progesterone receptors (77). In addition, it has been shown that androgens such as DHT or compounds with androgenic activity, such as MPA, can stimulate 17ß-HSD activity in favor of the formation of estrone from the more potent estrogen estradiol in human breast cancer lines (78). Consequently, alterations of enzymatic activities in the mammary tissue under the influence of locally produced steroids exerting androgenic action, may also account for the observed changes in the structure of the mammary gland.
In conclusion, the present study shows the potent stimulatory effects of androgens on lobuloalveolar as well as ductal development in the rat mammary gland. Furthermore, the histological changes of the mammary gland induced by DHEA treatment provide evidence for its intracrine conversion into active sex steroids with predominant or even possibly exclusive androgenic activity in the mammary gland. Local formation of androgens and estrogens through intracrine activity plays a major role in the pathophysiology of both normal and tumoral hormone-sensitive mammary tissue in the human. Considering the predominant androgenic action of DHEA on normal mammary tissue as well as the well recognized and potent inhibitory action of DHEA on the development and growth of DMBA-induced mammary tumors, which is mainly considered an androgenic effect, we suggest that tissue DHEA metabolism plays an important role in the pathophysiology of the mammary gland and could be a useful preventive and therapeutic approach for breast cancer.
Received June 2, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-dimethyltestosterone) as
primary and secondary therapy of advanced breast cancer. Oncology 28:138–146[Medline]
)anthracene-induced rat mammary tumors by
controlled-release low-dose medroxyprogesterone acetate. Breast Cancer
Res Treatm 24:127–137
5-4 isomerase.
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