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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-1967
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 2 607-613
Copyright © 2006 by The Endocrine Society

Estrogen-Metabolizing Enzymes in Breast Cancers from Women over the Age of 80 Years

Naoko Honma, Kaiyo Takubo, Motoji Sawabe, Tomio Arai, Futoshi Akiyama, Goi Sakamoto, Toshiaki Utsumi, Noriko Yoshimura and Nobuhiro Harada

Research Team for Geriatric Diseases, Tokyo Metropolitan Institute of Gerontology (N.H., K.T.), Tokyo 173-0015, Japan; Department of Pathology, Tokyo Metropolitan Geriatric Medical Center (M.S., T.A.), Tokyo 173-0015, Japan; Department of Breast Pathology, Cancer Institute (F.A., G.S.), Tokyo 135-8550, Japan; and Departments of Surgery (T.U.) and Biochemistry (N.Y., N.H.), Fujita Health University School of Medicine, Toyoake 470-1192, Japan

Address all correspondence and requests for reprints to: Dr. Naoko Honma, Research Team for Geriatric Diseases, Tokyo Metropolitan Institute of Gerontology, Sakaecho 35-2, Itabashi-ku, Tokyo 173-0015, Japan. E-mail: nhonma{at}tmig.or.jp.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Aromatase, steroid sulfatase, and 17ß-hydroxysteroid dehydrogenase type 1 (HSD-1) peripherally up-regulate, whereas estrogen sulfotransferase (EST) and HSD-2 down-regulate, the synthesis of active and more potent estrogens. These estrogen-metabolizing enzymes (EMEs) are important in postmenopausal breast cancers, but have never been systematically examined in breast cancers of the elderly.

Objective and Design: mRNA levels of EMEs in cancerous and normal breast tissues from 39 elderly patients (age, 80–99 yr) were compared with those from 39 controls (age, 37–70 yr) or compared according to estrogen (ER)/progesterone (PR) receptor status.

Results: Aromatase levels were higher in cancers of the elderly (EldCa) than in normal tissue of the elderly (P = 0.0008) or cancers of controls (P = 0.0033). In contrast, levels of steroid sulfatase and EST were higher in cancers of controls than normal tissue of controls (P = 0.0046 and P < 0.0001, respectively) or EldCa (P = 0.0001 and P < 0.0001, respectively). Levels of HSD-1 and HSD-2 did not differ significantly between any two of the categories. Among EldCa, HSD-1 levels were higher in ER/PR-positive than in ER/PR-negative carcinomas, whereas EST and HSD-2 exhibited opposite results.

Conclusions: The importance of aromatase is relatively increased in EldCa. ER/PR-positive EldCa exhibited a pattern of EMEs more beneficial to the production of estrogen than did ER/PR-negative EldCa. The specific pattern exhibited in EldCa may elucidate the role of EMEs in the absence of ovarian estrogens in the pathogenesis of breast cancer.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
ESTROGEN PLAYS IMPORTANT roles in the pathogenesis and development of breast cancer (1), and various kinds of hormonal therapy have been developed to treat the disease. In postmenopausal women, in whom ovarian function has decreased, the peripheral metabolism and biosynthesis of estrogens via estrogen-metabolizing enzymes (EMEs) are important. EMEs include aromatase (2, 3, 4, 5), steroid sulfatase (STS) (5, 6, 7, 8), estrogen sulfotransferase (EST) (6, 8), 17ß-hydroxysteroid dehydrogenase type 1 (HSD-1) (4, 9), HSD-2 (9), and HSD-5 (10). Aromatase converts circulating androgens from the adrenal gland or ovary into estrogens, that is, androstenedione into estrone (E1) or testosterone into 17ß-estradiol (E2) (2). STS hydrolyzes biologically inactive estrogen sulfates to produce active estrogens, whereas EST sulfonates estrogens to produce estrogen sulfates (5, 6). HSD-1 catalyzes the 17ß-reduction of a biologically weak estrogen, E1, to the most potent estrogen, E2, whereas HSD-2 catalyzes the oxidation of E2 to E1 (4, 9). In short, aromatase, STS, and HSD-1 up-regulate, whereas EST and HSD-2 down-regulate, the synthesis of active and more potent estrogens. Chemicals that modulate the actions of these enzymes and control the in situ biosynthesis of estrogens have been developed as potential medications for breast cancer (11, 12, 13, 14, 15, 16, 17). The application of aromatase inhibitors is already a standardized treatment for postmenopausal breast cancers (12, 13, 14).

In the elderly, general anesthesia or major surgery can be detrimental to activities of daily living, causing dementia or a bedridden state. For the treatment of breast cancer in the elderly, then, lumpectomy with appropriate adjuvant hormonal therapy has been desired. However, EMEs in elderly patients with breast cancer have never been systematically studied. In the present study, mRNA levels of EMEs in breast cancers from women over the age of 80 yr are examined and compared with those from younger women or normal breast tissues. A previous study revealed that the incidence of apocrine carcinoma and mucinous carcinoma, which are rare histological types of breast carcinoma, is much higher in the elderly (18). Hormone receptor status is distinctly different in these carcinomas from that in common breast carcinomas; most apocrine carcinomas are positive for the androgen receptor rather than estrogen receptor (ER) or progesterone receptor (PR), suggesting the involvement of androgens in apocrine carcinomas (18, 19, 20, 21), whereas most mucinous carcinomas are ER/PR positive (22, 23). Patterns of EMEs were compared according to histological type or ER/PR status among breast cancers of the elderly. Because most breast cancers of the elderly are considered to have developed in the absence of ovarian estrogens, such a study may elucidate the role of EMEs in the pathogenesis of breast cancer.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Materials for this study were obtained from 39 Japanese patients over the age of 80 yr (range, 80–99 yr; mean, 86 yr) and 39 Japanese patients, aged 37–70 yr (mean, 53 yr) with primary breast cancers who underwent curative surgery at the Tokyo Metropolitan Geriatric Medical Center and Fujita Health University Hospital, respectively, between 1999 and 2003. All tumors were histologically classified by pathologists (N.H., K.T., and G.S.) according to the World Health Organization classification (24). Of the 39 cancers of the elderly, 24, eight, five, and two were classified as invasive ductal carcinoma, apocrine carcinoma, mucinous carcinoma, and invasive lobular carcinoma, respectively, whereas all 39 cancers of the control group were classified as invasive ductal carcinoma. Immediately after surgical removal, the specimens of both tumor tissues and normal tissues were frozen in liquid nitrogen and then stored at –80 C before use. Normal tissue samples were obtained from a site as distant as possible from the tumor. Normal breast tissues were available in 37 elderly and 39 control cases. Materials were classified into four categories: cancers from the elderly (EldCa), normal tissues from the elderly (EldNorm), cancers from controls (ContCa), and normal tissues from controls (ContNorm). The study protocol was approved by the Tokyo Metropolitan Institute of Gerontology ethics committee.

Quantification of EME mRNA

Frozen tissues were homogenized as previously reported (7), and total RNA fractions were prepared from the homogenates as described by Chirgwin et al. (25). Fluorometric quantification was performed to determine the absolute mRNA content using fluorescence dye-labeled primers in the presence of an internal standard for each gene: aromatase, STS, EST, HSD-1, and HSD-2 (26, 27). To prepare the internal standard RNA, modified cDNAs for each gene were constructed by inserting 20- to 30-bp DNA fragments between the two PCR primer sites. The internal standard RNAs were synthesized in vitro with T7 RNA polymerase using the modified cDNAs as templates. Total RNA mixed with a known amount of internal standard RNA was subjected to RT with SuperScript II ribonuclease H– reverse transcriptase (Invitrogen Life Technologies, Inc., Carlsbad, CA) and each primer specific for the genes at 42 C for 40 min (Table 1Go). The resulting cDNAs were amplified by PCR using fluorescence-labeled (6-carboxyfluorescein; PerkinElmer, Foster City, CA) sense and antisense primers (Table 1Go). The fluorescent PCR products were electrophoresed in a 2% agarose gel and analyzed with an ABI PRISM 377 DNA sequencer (Applied Biosystems, Foster City, CA) and GeneScan 3.1.2 (Applied Biosystems). The amount of each mRNA was calculated from the peak areas of the fluorescent products by the internal standard method.


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  		TABLE 1. Oligonucleotides used for reverse transcription (RT) and PCR

 
Immunohistochemistry

Representative slides of primary cancers were selected for immunohistochemical examination. Antigen retrieval was performed by boiling the sections to be immunostained for ER and PR for 2 min in 10 mM citrate buffer (pH 6) using a pressure cooker. After blocking nonspecific activity, the sections were incubated with prediluted anti-ER mouse monoclonal antibody (clone 1D5, DakoCytomation, Carpinteria, CA) or prediluted anti-PR mouse monoclonal antibody (clone 1A6, DakoCytomation). Incubation for the anti-ER and -PR antibodies was performed for 60 min at room temperature. ChemMate Envision (DakoCytomation) was used for all immunohistochemical stains. A positive control slide whose immunoreactivity had been confirmed and a negative control slide to which subclass-matched control IgGs were applied instead of the specific monoclonal antibody were included in each batch.

The results of the immunological staining were assessed by two pathologists (N.H. and K.T) independently; where discrepancies occurred, the cases were discussed. Immunoreactivities for ER and PR were scored independently by evaluating the percentage of positively stained cancer cells regardless of intensity; nuclear immunoreactivity in 10% or more of the cancer cells was considered positive according to the St. Gallen Consensus 2003 (28).

Statistics

Statistical analyses were carried out using StatView 5.0 (SAS Institute, Inc., Carey, NC). Mean levels of EME mRNA were compared as follows: EldCa vs. EldNorm, ContCa vs. ContNorm, EldCa vs. ContCa, and EldNorm vs. ContNorm. Among EldCa, mean levels of EME mRNA were also compared between different histological types. A one-factor ANOVA was used for the comparison of multiple groups, and Scheffé’s test was used for comparisons between two groups. Student’s t test was used for comparison of mean levels of EME mRNA among invasive ductal carcinomas according to ER or PR status. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Comparison of EME mRNA levels: EldCa vs. EldNorm, ContCa vs. ContNorm, EldCa vs. ConCa, and EldNorm vs. ContNorm

Mean levels of EME mRNA obtained for EldCa, EldNorm, ContCa, and ContNorm are shown in Fig. 1Go. Comparisons were made among the four categories (by one-factor ANOVA) as well as between EldCa and EldNorm, between ContCa and ContNorm, between EldCa and ContCa, and between EldNorm and ContNorm (by Scheffé’s test).


Figure 1
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  		FIG. 1. Comparison of EME mRNA levels among EldCa, EldNorm, ContCa, and ContNorm. Arom, Aromatase. Bar, SEM. {dagger}, P < 0.1; *, P < 0.01; **, P < 0.001; ***, P < 0.0001.

 
Aromatase mRNA levels were significantly different among the four categories (P < 0.0001). For cancerous and normal tissues, EldCa exhibited significantly higher aromatase levels than did EldNorm (P = 0.0008), whereas there was no significant difference between ContCa and ContNorm (P = 0.3007). Concerning the elderly and controls, EldCa exhibited significantly higher aromatase levels than did ContCa (P = 0.0033), whereas there was no significant difference between EldNorm and ContNorm (P = 0.5572; Fig. 1Go).

STS mRNA levels differed significantly among the four categories (P < 0.0001). There was no significant difference between EldCa and EldNorm (P = 0.9244), whereas ContCa exhibited significantly high STS levels compared with ContNorm (P = 0.0046). STS levels were significantly lower in EldCa than ContCa (P = 0.0001), whereas there was no significant difference between EldNorm and ContNorm (P = 0.3811; Fig. 1Go).

EST mRNA levels differed significantly among the four categories (P < 0.0001). EST mRNA was undetectable in 31 of 39 EldCa and 30 of 37 EldNorm, resulting in almost negligible EST levels for EldCa and EldNorm compared with ContCa. There was no significant difference between EldCa and EldNorm (P > 0.9999), whereas ContCa exhibited significantly increased EST levels compared with ContNorm (P < 0.0001). EldCa exhibited significantly lower EST levels than ContCa (P < 0.0001), whereas there was no significant difference between EldNorm and ContNorm (P = 0.4986; Fig. 1Go).

HSD-1 mRNA levels also differed significantly among the four categories (P = 0.0266). Similar to EST, EldCa and EldNorm exhibited almost negligible HSD-1 levels compared with ContCa, nearly resulting in a significant difference between EldCa and ContCa (P = 0.0793). There was no significant difference between EldCa and EldNorm (P > 0.9999), between ContCa and ContNorm (P = 0.2006), or between EldNorm and ContNorm (P = 0.9732; Fig. 1Go).

There was no significant difference in HSD-2 mRNA levels among the four categories (P = 0.1154) or between any two of the four categories (Fig. 1Go).

Comparison of EME mRNA levels and hormone receptor status according to histological type among EldCa

mRNA levels of aromatase or STS significantly differed among the four histological types (P = 0.0395 and P = 0.0126, respectively), whereas those of EST, HSD-1, and HSD-2 did not (P = 0.6273, P = 0.6740, and P = 0.8555, respectively). No significant differences were observed in most comparisons between two of the four histological types; however, some features emerged (Fig. 2Go). Mucinous carcinoma exhibited a higher aromatase mRNA level than invasive ductal carcinoma (P = 0.0905), whereas mRNA of EST and HSD-2 was detectable in none and only one of five cases, respectively. Apocrine carcinoma showed no distinct difference from invasive ductal carcinoma, except that it exhibited a significantly higher STS mRNA level (P = 0.0339). Invasive lobular carcinoma exhibited the lowest mRNA levels for all EMEs among the four histological types, although there were only two cases of invasive lobular carcinoma.


Figure 2
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  		FIG. 2. Comparison of EME mRNA levels according to histological type among breast cancers of the elderly. Apo, Apocrine carcinoma; Arom, aromatase; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; Muc, mucinous carcinoma. Bar, SEM. {dagger}, P < 0.1; *, P < 0.05.

 
The hormone receptor status of EldCa according to histological type as well as that of the other categories are shown in Table 2Go. None of the eight apocrine carcinomas exhibited positivity for either ER or PR, whereas all five mucinous carcinomas were positive for ER. Twenty-one (88%) and 15 (63%) of the invasive ductal carcinomas exhibited positivity for ER and PR, respectively. In total, 27 (69%) and 18 (46%) EldCa exhibited positivity for ER and PR, respectively.


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  		TABLE 2. Hormone receptor status of each category and breast cancers of the elderly according to histological type

 
Comparison of EME mRNA levels according to hormone receptor status among invasive ductal carcinoma

Because apocrine carcinoma and mucinous carcinoma are special histological types of breast carcinoma, and their hormone receptor status is far different from that of invasive ductal carcinoma, EME mRNA levels among invasive ductal carcinomas of EldCa were studied separately according to hormone receptor status (Fig. 3Go). Aromatase and STS exhibited no significant difference according to ER/PR status. HSD-1 mRNA levels were higher in ER/PR-positive carcinomas, whereas mRNA levels of EST and HSD-2 exhibited the opposite results, with significant differences for HSD-2 according to ER status (P = 0.0001) and for EST and HSD-1 according to PR status (P = 0.0428 and P = 0.0215, respectively), and almost a significant difference for HSD-2 according to PR status (P = 0.0674).


Figure 3
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  		FIG. 3. Comparison of EME mRNA levels according to hormone receptor status among invasive ductal carcinomas of the elderly. Arom, Aromatase. Bar, SEM. {dagger}, P < 0.1; *, P < 0.05; **, P < 0.0001.

 
EME levels did not differ significantly according to hormone receptor status in ContCa, all of which were classified as invasive ductal carcinoma (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
For cancerous and normal tissues, EldCa exhibited significantly higher aromatase levels than EldNorm, whereas levels of the other EMEs did not differ significantly between EldCa and EldNorm. In contrast, ContCa exhibited significantly high levels of STS and EST, but not aromatase, compared with ContNorm. Comparing the elderly and controls, EldCa exhibited significantly higher aromatase levels than ContCa, whereas levels of STS and EST were significantly lower in EldCa than ContCa. In contrast with STS, EST was undetectable in most EldCa and EldNorm. HSD-1 and HSD-2 did not differ significantly between any two of the four categories; however, a significant difference was almost achieved for HSD-1 between EldCa and ContCa.

The present results suggest that aromatase plays a relatively important role in the pathogenesis of breast cancer in the elderly in the five EMEs examined. Basal aromatase levels in peripheral stroma have been reported to be increased in the elderly (29, 30, 31); however, there was no significant difference in aromatase levels between EldNorm and ContNorm in the present study. This suggests that the higher aromatase level in EldCa than ContCa is not merely caused by aging, and that production of aromatase is accelerated in EldCa. Although levels of both STS and EST were significantly lower in EldCa than ContCa, EST mRNA was undetectable in most EldCa, whereas STS mRNA was detectable in all EldCa. Considering the balance of STS and EST, STS appears to dominate EST in EldCa, and this balance may promote the production of active estrogen.

Although there have been various strategies to reduce local production of estrogens (11, 12, 13, 14, 15, 16, 17), inhibiting aromatase seems to be most effective in EldCa, considering that aromatase levels were significantly higher in EldCa than in any other category. Despite the low STS levels in EldCa, the possibility of using an STS inhibitor (15, 16, 17) to treat EldCa should not be excluded, because STS dominates EST and seems to play a role in the production of active estrogens in EldCa. A comparative study is needed to clarify which EME modulator would be most effective in treating breast cancer in the elderly.

Levels of both STS and EST were highest in ContCa. Considering the balance of STS and EST, their net effect to produce active estrogen may be smaller in ContCa than EldCa. Falany and Falany (32) reported that EST activity is greater in normal breast epithelial cells than breast cancer cells and hypothesized that the loss of EST activity by the tumor tissue promotes estradiol formation and tumor growth in ER-positive tumors. This contradicts the present finding that EST levels were significantly higher in ContCa than ContNorm. The discrepancy may be partly explained by the subjects examined, because they dealt with several cell lines whose origin is unknown. The importance of the loss of EST activity in ER-positive breast cancers suggested by Falany and Falany (32), however, is also supported in EldCa, especially in ER/PR-positive EldCa as described below, because EST was undetectable in most of them. Because ContCa exhibited significantly higher STS levels than either ContNorm or EldCa, STS inhibitors (15, 16, 17) may be effective for the treatment of breast cancer in early postmenopause, increasing the relative dominance of EST.

There have been many studies examining the expression of EMEs in breast carcinomas; however, a significant difference was not observed according to age or menopausal status in most of these studies (2, 3, 4, 5, 6, 7, 8, 9). Some researchers reported that aromatase levels were apt to be, although not significantly, higher in postmenopausal than in premenopausal breast cancer (27). In the present study EldCa showed a distinct difference in EME levels from ContCa, probably because the study dealt with a number of extremely postmenopausal cases, in which ovarian function is markedly reduced throughout carcinogenesis and development of breast cancer.

A previous study has revealed that the incidence of apocrine carcinoma and mucinous carcinoma is high in breast cancers from elderly women (18). The present study also included eight apocrine carcinomas and five mucinous carcinomas among 39 EldCa. The hormone receptor status observed here is consistent with that in other studies; none of the apocrine carcinomas and all of the mucinous carcinomas were ER/PR positive (18, 19, 20, 21, 22, 23, 33). EME levels differed according to histological type, although the difference was not significant, with some exceptions, probably because the number included in each histological type was limited. Mucinous carcinoma seems to have a more favorable EME pattern for the production of active and more potent estrogens: higher aromatase and almost undetectable EST or HSD-2 levels compared with the other histological types. This finding is compatible with all mucinous carcinomas being ER positive and seemingly estrogen dependent. Although apocrine carcinomas exhibited significantly high STS levels compared with invasive ductal carcinomas, the significance is not known, because none of them was ER/PR positive. Considering that most apocrine carcinomas exhibit ERß positivity (Honma, N., K. Takubo, F. Akiyama, F. Kasumi, T. Arai, T. Hosoi, N. Yoshimura, N. Harada, M. Younes, and G. Sakamoto, unpublished observation), the significance of estrogens in apocrine carcinoma should not be ignored at present when the role of ERß remains to be revealed (34). Furthermore, because most apocrine carcinomas are positive for the androgen receptor (18, 19, 20, 21), STS may have a more important role in hydrolyzing dehydroepiandrosterone sulfate than in hydrolyzing estrogen sulfates in apocrine carcinomas. The hormone dependence of apocrine carcinomas, on which sex steroid hormones are dependent, should be further examined. Those specific EME patterns may have developed carcinomas of specific histological types.

When invasive ductal carcinomas of EldCa were studied separately, levels of EST, HSD-1, and HSD-2 exhibited (sometimes significant) differences according to hormone receptor status, whereas those of aromatase and STS did not. The findings that ER/PR-positive carcinomas exhibited lower levels of EST, higher levels of HSD-1, and lower levels of HSD-2 are reasonable, because this means that the pattern of EMEs favorable for E2 production was frequently observed in estrogen-dependent carcinomas. Such phenomena have not been reported previously and were not observed in ContCa in the present study. Furthermore, EST expression has been reported to positively correlate with ER/PR expression (35, 36), in contrast to the present results. The discrepancy seems to be caused by a difference in subjects, because the present study dealt with a number of breast cancers in the very elderly, who are free from ovarian function and in whom EMEs are almost the sole source of estrogens, throughout the carcinogenesis and development of the diseases. The expression of HSD-2 has been reported to be up-regulated by progesterone-PR interaction in the endometrium (37, 38). If this were also true for the breast, the present finding that HSD-2 levels are higher in PR-negative EldCa might contradict those observations. However, because there is no luteal phase in elderly women, and progesterone remains at low levels, the up-regulation of HSD-2 expression by progesterone-PR interaction is not likely to occur in these women. Those differences in subject, tissue, and age may explain the discrepancy compared with other studies. In any case, EST, HSD-1, and HSD-2 may play a role in increasing E2 production in ER/PR-positive carcinomas, balancing one another.

In the present study the results are limited to measurements of mRNA. Because the actual activity may be altered by posttranslational effects and the availability of cofactors, a measure of enzyme concentrations or enzyme activity is needed to confirm the present results. Other EMEs, such as HSD-5, were not included in the study. Because HSD-5 has been shown to have potential importance in the breast (10), additional studies that includes this enzyme should be conducted to thoroughly elucidate the metabolism of estrogen in EldCa.

In conclusion, this is the first study to systematically examine EME levels in breast cancers from elderly women. Aromatase levels were significantly higher in EldCa than EldNorm, whereas levels of STS and EST did not differ significantly between the two groups. Aromatase levels were relatively higher in EldCa than ContCa, whereas STS, EST, and HSD-1 exhibited the opposite results. The importance of aromatase is relatively increased in EldCa. Despite low levels of STS and EST, STS dominated EST in EldCa. The pattern of EMEs differed according to histological type or ER/PR status in EldCa, which is reasonable considering the effects of estrogen production and estrogen dependency of carcinomas. This study of EMEs in breast cancer from the extreme elderly has at least partly elucidated the role of EMEs in the pathogenesis of breast cancer in the absence of ovarian function. Additional study is needed to clarify which EME modulator is the most effective for treating elderly patients with breast cancer.


   Footnotes
 
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan.

First Published Online November 22, 2005

Abbreviations: ContCa, Cancers of controls; ContNorm, normal tissue of controls; E1, estrone; E2, 17ß-estradiol; EldCa, cancers of the elderly; EldNorm, normal tissue of the elderly; EME, estrogen-metabolizing enzyme; ER, estrogen receptor; EST, estrogen sulfotransferase; HSD-1, 17ß-hydroxysteroid dehydrogenase type 1; PR, progesterone receptor; STS, steroid sulfatase.

Received September 1, 2005.

Accepted November 15, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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