Figure 1. The key reactions in the metabolism of estrogens and androgens.
A-dione = androstenedione; 17HSD1, 2 etc. refer to different 17HSD-enzymes;
P450arom = P450 aromatase enzyme.
Cancer Therapy Vol 3, 543-550, 2005
17b-hydroxysteroid
dehydrogenases and breast cancer
Pirkko Vihko1,2,*
and Veli Isomaa1
1Research Center for
Molecular Endocrinology and WHO Collaborating Centre, Biocenter Oulu, P.O. Box
5000, FI-90014 University of Oulu, Finland
2Department
of Environmental Sciences, Division of Biochemistry, FI-00014 University of
Helsinki, Finland
__________________________________________________________________________________
*Correspondence: Professor Pirkko Vihko, M.D., Ph.D., Research Center for Molecular
Endocrinology and WHO Collaborating Centre, Biocenter Oulu, P.O. Box 5000,
FI-90014 University of Oulu, Finland; Tel: +358-40-5431734; Fax: +358-8-3155631; e-mail: pirkko.vihko@oulu.fi
Key words: 17b-hydroxysteroid
dehydrogenases, breast cancer, hormonal treatment
Abbreviations:
17b-hydroxysteroid
dehydrogenases, (17HSDs); dihydrotestosterone, (DHT); estrogen receptor a, (ERa);
estrogen receptor b,
(ERb);
progesterone receptor, (PR); Tumor-Node-Metastasis, (TNM)
Summary
Experimental
data suggest that ovarian sex steroids, particularly estrogens but also
progesterone, have important roles in the development of breast cancer. The
biological activity of female sex steroids in target tissues such as the breast
is regulated by several enzymes, including 17b-hydroxysteroid dehydrogenases (17HSDs). Changes in
the expression patterns of these enzymes may significantly modulate the
intracellular steroid hormone activity and concentration and, therefore, play a
pathophysiological role in malignant transformation. Estrogen influence is one
important focus of breast cancer therapies. We have previously shown that
estradiol-producing 17HSD type 1 and estradiol-inactivating type 2 are present
in normal breast tissue, breast cancer and breast cancer cell lines. To further
clarify the role of 17HSDs in breast cancer, we recently analyzed the mRNA expressions
of the 17HSD type 1, 2 and 5 enzymes in 794 breast carcinoma specimens. Both
17HSD type 1 and 2 mRNAs were detected in normal breast tissue from
premenopausal women but not in specimens from postmenopausal women. 17HSD type
5 mRNA was present in the normal breast of both pre- and postmenopausal women.
Of the breast cancer specimens, 16 % showed signals for 17HSD type 1 mRNA, 25 %
for type 2 and 65 % for type 5. No association between the 17HSD type 1, type 2
and type 5 expressions was detected. The patients with tumors expressing 17HSD
type 1 mRNA or protein had significantly shorter overall and disease-free
survival than the other patients. The expression of 17HSD type 5 was
significantly higher in breast tumor specimens than in normal tissue. Cox multivariate
analyses showed that tumor size, 17HSD type 1 mRNA and estrogen receptor a (ERa) had
independent prognostic significance. Our data show that 17HSD type 1 expression
is associated with a poor prognosis and support the idea that inhibition of this
enzyme could be a beneficial therapy for breast cancer patients.
Breast cancer is the most common malignant disease in
the western countries and its incidence is increasing (Greenlee et al, 2001).
Exposure to elevated concentrations of estrogens is associated with the
etiology of this hormone-associated cancer. Epidemiological and endocrine
evidence indicates that estrogens have a proliferative effect on breast
epithelium, but the exact mechanism in the development and progression of breast
cancer is not known. The apparent role of progesterone in the control of the
cell cycle is not known, but in adult, non-pregnant breast epithelial
proliferation is maximal about one week after ovulation (Anderson et al, 1982).
At this stage of the menstrual cycle both estradiol and progesterone
concentrations are high. Further, both estrogen and progesterone increase the
proliferation of breast cancer cells in in
vitro assays (Lippman et al, 1976; Cullen and Lippman 1989; Musgrove et al,
1991).
In premenopausal women, the ovary is the main source
of estrogens, but estrogenic steroids are also formed in peripheral tissues.
After menopause, all estrogens are formed locally. The peripheral tissues are
not capable of performing de novo
steroid synthesis but contain the enzymes needed for the formation of active
androgens and estrogens form adrenal-derived C19 steroids, such as
dehydroepiandrosterone, its sulphate and androstenedione, which are abundantly
secreted into the circulation in humans (Labrie et al, 1997). These steroids
serve as substrates in peripheral tissues and locally produced active steroids
exert their action in the intracrine manner on the same cell in which they are
synthesized without diffusion into the circulation and, therefore, effectively
regulate sex steroid influence at the pre-receptor level in the target cells.
The enzymes modulating sex steroid metabolism and, consequently, the
concentration of active steroids in peripheral tissues include steroid
sulphatases, 3b-hydroxysteroid dehydrogenases,
3a-hydroxysteroid dehydrogenases, aromatase, 17b-hydroxysteroid dehydrogenases and 5a-reductases.
We have focused our studies on 17b-hydroxysteroid dehydrogenases (17HSDs), which
regulate the biological activity of sex steroid hormones by catalyzing the
interconversions between highly active steroid hormones, e.g. estradiol and testosterone and corresponding less active
hormones, estrone and androstenedione (Figure
1). Up till now, at least nine different 17HSD isoenzymes, namely the types
1-5, 7-8 and 10-11 (Peltoketo et al, 2003; Mindnich et al, 2004), have been
characterized in humans. In intact cells, the types 1, 3, 5 and 7 mainly
catalyze reductive reactions, whereas the other types are considered as
oxidative enzymes. The presence of a series of 17HSD enzymes with cell-specific
expression patterns and differential substrate specificities point to the
important role of 17HSDs in intracrine steroid formation.
II. Enzymatic
characteristics of human 17HSD type 1, type 2, type 5 and
type 7
Human 17HSD type 1 catalyzes the reduction of estrone
to estradiol (Puranen et al, 1997), preferring the phosphorylated form of
nicotinamide-adenine dinucleotide, NADPH, as a cofactor. In cultured cells, the human type 1 enzyme is also capable of
reducing androstenedione and 5a-androstanedione
to some extent, but it clearly gives preference to phenolic substrates over
androgens. 17HSD type 1 is essential for estradiol production and it is most
abundantly expressed in the granulosa cells of the ovary (Ghersevich et al,
1994; Sawetawan et al, 1994) and the syncytiotrophoblasts of the placenta
(Fournet-Dulguerov et al, 1987; Mentausta et al, 1990), which secrete
estradiol into the circulation. In addition, the type 1 enzyme contributes to
the estrogen response by converting estrone to estradiol locally in certain
targets of estrogen action, such as normal and malignant breast tissue
(Poutanen et al, 1995; Miettinen et al, 1996a).
17HSD type 2 is
involved in the inactivation of estradiol, testosterone and dihydrotestosterone
(DHT) and the activation of progesterone. 17HSD type 2 is expressed in a wide
variety of tissues, such as breast, uterus, prostate, placenta, liver,
intestine and kidney (Peltoketo et al, 1999; 2003). Typically, the type 2
enzyme is expressed in epithelial cells, such as the surface epithelial cells
of the gastrointestinal and urinary tracts (Mustonen et al, 1998a; Oduwole et
al, 2003). The type 2 enzyme may restrict the access of active sex steroids
into the circulation and it may protect the target tissues of hormonal action
against excessive sex hormone influence by catalyzing the conversion of
androgens and estrogens into less active forms. In the placenta, the type 2 enzyme may limit the access of fetal
androgens into the maternal tissue and the access of maternal estrogen into the
fetus, acting as a barrier between the fetus and the mother (Mustonen et al,
1998b, Li et al, 2005).
Figure 1. The key reactions in the metabolism of estrogens and androgens.
A-dione = androstenedione; 17HSD1, 2 etc. refer to different 17HSD-enzymes;
P450arom = P450 aromatase enzyme.
Unlike other
17HSDs, which belong to the short-chain dehydrogenase/reductase superfamily,
17HSD type 5, a reductive 17HSD, is a member of the aldo-keto reductase
superfamily (Dufort et al, 1999; Luu-The et al, 2001). 17HSD5 has a broad tissue distribution and it recognizes several
different substrates in in vitro
assays (Luu-The et al, 2001; Penning et
al, 2001). 17HSD5 has some activity as a reductase of 3-keto and
17-keto and as an oxidase of 3a-
and 17b-hydroxysteroids (Penning et al, 2001). Human 17HSD5 also has
a high level of 20a-hydroxysteroid
dehydrogenase activity, which inactivates progesterone to 20a-OH-progesterone (Luu-The et al,
2001). In myeloid leukemia cell lines, this enzyme possesses marked
11-ketoreductase activity, converting prostaglandin D2 to PGF2a and functions to regulate cell differentiation (Desmond et al, 2003). So far, little is known about the role
of 17HSD5 in breast tissue, but it may be involved in the metabolism of female
sex steroids. In the prostate, 17HSD5 catalyzes the formation of testosterone
and the inactivation of DHT (Dufort et
al, 1999).
Human 17HSD type 7 is a membrane-associated reductive
enzyme converting estrone to estradiol and DHT to an estrogenic metabolite, 5a-androstane-3b, 17b-diol, thereby catalyzing the reduction of the keto
group in either the 17- or the 3-position of the substrate. Minor 3b-HSD-like activity towards progesterone and 20a-hydroxyprogesterone, leading to inactivation of
progesterone by 17HSD type 7, has also been detected (Trn et al, 2003). Human
17HSD type 7 is expressed in steroidogenic cells and several peripheral
tissues, such as liver, lung and thymus. Its function is not known, but it may
be responsible for the local production of estrogenic metabolites in peripheral
tissue (Trn et al, 2003). 17HSD type 7 has also other substrates apart from
sex steroids (Breitling et al, 2001). It was shown that the enzyme acts as a
3-ketosteroid reductase in cholesterol biosynthesis, converting zymosterone to
zymosterol (Marijanovic et al, 2003).
Estrogens are essential for the growth and
differentiation of the mammary gland. The female mammary gland undergoes a
surge of cell divisions during puberty. There is also cyclic proliferation and
involution in the breast during the menstrual cycle throughout adult life
(Russo et al, 1999). Multiplication of normal breast cells cultured in vitro is increased by the addition of
estradiol to the culture (Mauvais-Jarvis et al, 1986). Further, the phenotypes
of estrogen receptor a (ERa) and b
(ERb) knockout mice indicate that ERa is important for the growth and development of the
mammary gland, whereas ERb is involved in the
terminal differentiation of glandular epithelium (Couse and Korach 1999; Foster
et al, 2002).
Breast cancer is the most common malignant neoplastic
disease in the female. The majority of breast carcinomas are invasive ductal or
lobular carcinomas. Several endocrine and reproductive factors, such as early
age at menarche, nulliparity, or delayed first childbirth, late age at
menopause and obesity, are associated with its etiology (Vihko and Apter 1989).
Premature loss of ovarian function greatly reduces the breast cancer risk,
supporting the idea that ovarian hormones are important factors in breast
carcinogenesis. While the exact mechanisms of estrogen action in breast cancer
development remain to be elucidated, it has been shown that estrogens induce
and promote mammary cancer in rodents (Nandi et al, 1995) and exert
proliferative effects on cultured human breast cancer cells (Cullen and Lippman
1989). A positive correlation between the plasma estrogen concentration and the
breast cancer risk has been observed in postmenopausal women (Tonilo et al,
1995; Berrino et al, 1996; Hankinson et al, 1998). The majority of breast
cancers, however, are detected during the postmenopausal period, when the
ovaries have ceased to produce estrogens. Despite the low circulating estrogen
concentrations in these patients, the tissue concentrations of estrogens in the
breast are higher and, further, the estradiol concentration has been shown to
be significantly higher in breast tumors than in normal breast tissue
(Vermeulen et al, 1986; Pasqualini and Chetrite 2002). The proliferation of
breast epithelial cells is maximal during the second half of the menstrual
cycle, at the time when both estradiol and progesterone are secreted (Anderson
et al, 1982) suggesting that also progesterone may have a role in the development
of breast cancer.
Both 17HSD type 1 and type 2 are expressed in the
epithelium of normal breast tissue in premenopausal women (Miettinen et al,
1999) and oxidative activity seems to be the dominant form in non-tumorous
cells (Miettinen et al, 1999, Spiers et al, 1998). The type 1 enzyme is
expressed in the epithelial cells of ducts and alveoli throughout the menstrual
cycle. Breast cancer cell lines have been shown to express 17HSD type 1, 17HSD
type 2, or both enzymes (Miettinen et al, 1996b).
We recently analyzed the mRNA expressions of the 17HSD
type 1, type 2 and type 5 enzymes were analyzed in 794 breast carcinoma
specimens by using tissue microarrays and normal histological sections. The
results were correlated with ERa
and ERb, progesterone receptor (PR), Ki67 and c-erbB-2
expressions analyzed by immunohistochemical techniques and the the
Tumor-Node-Metastasis (TNM) classification, tumor grade, disease-free interval
and survival of the patients (Oduwole et al, 2004).
Both 17HSD type 1 and type 2 mRNAs were detected in the
normal breast tissue of premenopausal women, but no expression of 17HSD type 1
or 17HSD type 2 mRNA was observed in the normal tissue specimens from
postmenopausal women. The mRNAs were localized in the ductal or lobular epithelial
cells (Oduwole et al, 2004).
In malignant breast lesions, variable expression
patterns for 17HSD type 1 and type 2 mRNA were observed (Figure 2). There were 16 % 17HSD type 1 mRNA and 25 % type 2 mRNA
positive cases. No significant differences were observed for the 17HSD type 1
enzyme in malignant tissue between the pre- and postmenopausal groups. In
contrast, the number of cases showing signals for 17HSD type 2 mRNA was higher
in the premenopausal than the postmenopausal patients. There was a moderate
agreement between the in situ
hybridization results and immunohistochemistry of 17HSD type 1. The 17HSD type
1 positive breast cancer specimens accounted for 20 % of all cases in
immunohistochemical analysis and for 16 % in in situ hybridization (Oduwole et al, 2004).
17HSD type 5 mRNA expression was detected in the
epithelial cells of normal and malignant breast tissue specimens from both pre-
and postmenopausal women. However, the expression of 17HSD type 5 was
significantly higher in breast cancer specimens than in normal breast tissue (Figure 3). Altogether 65% of the breast cancer specimens were positive for 17HSD
type 5 expression. Our data showed no
correlation between 17HSD type 1 and type 2 and/or type 5 (Oduwole et al,
2004).
No association was found between 17HSD type 1, type 2
and type 5 mRNA expression and tumor grade. 17HSD type 1 mRNA expression did
not associate with TNM status. Similar observations were made for 17HSD type 2
mRNA. The
overexpression of 17HSD type 5 was associated with N but not with T or M
status.
A significant association was observed between ERa and ERb expression. There was also a significant inverse association between
ERa and 17HSD type 1 as well as ERa and 17HSD type 5. Tumors expressing 17HSD type 1,
type 2 and/or type 5 mRNA did not associate with the expression of Ki67 or with
c-erb-b2 status (Oduwole et al,
2004).
In benign breast tissue and breast cancer, variable
amounts of 17HSD type 1 and 17HSD type 2 enzyme proteins have been reported in
previous studies (Poutanen et al, 1992; Sasano et al, 1996; Suzuki et al, 2000;
Gunnarsson et al, 2001). While we detected 17HSD type 1 mRNA in about one fifth
of our specimens, some other studies have reported the presence of 17HSD type 1
enzyme protein in about half of the specimens. Gunnarsson et al, (2001), using
RT-PCR, detected 17HSD type 1 in all of the 84 archival breast cancer specimens
they studied. The reason for the discrepancies is not known, but it may be
partially explained by the different methodologies used and by the relatively
small patient series in most previous studies.
Figure 2. In situ hybridization of 17HSD1 in breast lesions from a pre- and a
postmenopausal woman. Strong signals for 17HSD1 mRNA (white arrows) in a ductal
invasive carcinoma in a premenopausal woman (A) Corresponding (H&E) stain with arrows indicating the margin
of the tumor area (B) Another case
of ductal invasive carcinoma from a postmenopausal woman showing strong signals
for 17HSD1 mRNA (C) A corresponding
H&E-stained slide of the same area (D)
The arrows indicate tumor cell islands among a heavy inflammatory infiltrate.
Magnification: x 100. Reproduced from Oduwole et al, 2004 with kind permission
from Cancer Research.
Figure 3. In situ hybridization of 17HSD5 in normal and malignant breast
tissue. Strong signals of 17HSD5 mRNA (arrows) in breast tumor cells (A).
Negative control using sense probe in the tumor area (B) Magnification: x 400. Low signals of 17HSD5 mRNA in normal
breast cells (C) Negative control
using sense probe (D) Magnification:
x 200. Reproduced from Oduwole et al, 2004 with kind permission from Cancer
Research.
As stated above, estrogens are known to be important
for the growth of breast cancer in both pre- and postmenopausal women.
Therefore, disruption of the estrogen-signaling pathway is an important
treatment strategy for breast cancer. Since peripheral estrogen production is
quantitatively the most important, systemic treatments are needed particularly
in postmenopausal women. Adjuvant systemic therapies, such as hormonal therapy
before and after surgery, have greatly improved the prognosis of breast cancer.
Two strategies have been widely used to decrease estrogen influence. One is the
use of antiestrogens, i.e. compounds that interact with the estrogen receptor,
such as tamoxifen. The efficacy of tamoxifen in the treatment of breast cancer
was first reported by Cole et al, 1971 and it has become the most widely used
endocrine therapy for breast cancer. Tamoxifen increases overall survival,
reduces recurrence and has minimal side effects (Early Breast Cancer TrialistsŐ
Collaborative Group, 1998).
Another strategy has been the use of aromatase
inhibitors, i.e. compounds inhibiting the conversion of androgens to estrogens
(Brodie, 2002). The use of aromatase inhibitors began in the 1980s and several
inhibitors, including both steroidal and nonsteroidal compounds, are in
clinical use.
High estradiol concentrations have been detected in
breast cancer tissue. In addition to aromatase, other enzymes, particularly
17HSD type 1, are involved in the production of active estradiol in breast
tissue. Since estrone sulfate is quantitatively the most important circulating
estrogen in pre- and postmenopausal women, the combined activities of estrone
sulfatase and 17HSD type 1 may be more important in local estradiol production
than aromatase activity in breast cancer tissue. Our data demonstrating that
17HSD type 1 is an independent prognostic factor in breast cancer support this
suggestion. Since high 17HSD type 1 expression is associated with a poor
prognosis, it is clear that inhibition of this enzyme could be a beneficial
therapy for breast cancer patients selected based on the expression of 17HSD
type 1 in tissue specimens.
This work was supported by the Research Council for Health
of the Academy of Finland (Project Nos. 47630 and 51618), the Finnish Cancer
Foundation and the Sigrid Juselius Foundation.
Figure 4. A, Kaplan-Meier curve
showing the survival of patients with breast carcinoma in relation to 17HSD1.
Patients with tumors expressing 17HSD1 mRNA had a significantly worse prognosis
(p=0.0010, log rank). B, Kaplan-Meier curve showing the disease-free interval
of breast carcinoma patients in relation to 17HSD1. Patients with 17HSD1 mRNA expressing
tumors has a significantly shorter disease-free interval than the other
patient. Reproduced from Oduwole et al, 2004 with kind permission from Cancer
Research.
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First row (in the back) from left to right: Riitta Kurkela,
Annakaisa Herrala, Toni Luokkala, Mirja Makelainen, Riikka Wirkkala, Ileana
Quintero, Svea Torn, Marja Kantola and Veli Isomaa.
Second row (in the middle) from left to right: Helena Kaija,
Anitta Pulkka, Anna Ronka, Airi Vesala and Paivi Harkonen.
In the front: Pirkko Vihko