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*Correspondence: Mahesh Kumar M.J, Scientist, Center for Cellular and Molecular Biology, Uppal Road, Hyderabad -500 007, India;
Tel:+ 91-40-27192872; Fax : +91-40-27160591; Email: mahesh73@ccmb.res.in
Key words: anti estrogenic therapy, blocking of estrogen receptor, estrogen synthesis inhibitor, estrogen receptor down regulator
Abbreviations: bone mineral density (BMD); estrogen receptor (ER); estrone (E1); estradiol (E2); estriol (E3); estrogen responsible
elements (ERS); multiple outcome of raloxifene evaluation (MORE); selective estrogen receptor modulator (SERM); selective estrogen
receptor down regulator (SERD)
Received: 17 June 2008; Revised: 21 August 2008
Accepted: 4 September 2008; electronically published: September 2008
Summary
Breast cancer is the leading malignancy worldwide. Estrogen and estrogen receptors (ER) play a major
role in breast cancer progression and development. In this review, our discussion is mechanism and action of
estrogen and its receptors in breast cancer. Also, this paper will summarize the therapeutic methods available for
anti hormonal therapy, molecular mechanism of action of anti hormonal agents, basic science of estrogen and
estrogen receptors and current status of chemoprevention with selective estrogen receptor modulators (SERM).
I. Introduction
III. Synthesis
Estrogen derivatives of estrone (E1), estradiol (E2),
and estriol (E3) (Figure 1), the C18 steroids are derived
from cholesterol. Cholesterol is taken up by steroidogenic
cells and stored and moved in to the site of steroid
synthesis (Scallen et al, 1985). The different steroids are
formed by reduction in the number of carbon atoms from
27 to 18 (Kallen et al, 1998).
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V. Functions
Estrogen stimulates growth, blood flow and water
retention in sexual organs and is also involved in breast
lipoprotein receptors, resulting in a decrease in serum
concentrations of low-density lipoprotein cholesterol in
the liver (Paganin et al, 1996). Estrogen is increasing the
potential for blood coagulation. In gastrointestinal tract,
estrogens may play role in protecting against colon cancer
(Calle et al, 1995) and it increases the turgor and collagen
production and reduces the depth of wrinkles on aged
(Schmidt et al, 1996). In breast tissue, estrogen stimulates
the growth and differentiation of the ductal epithelium,
induces mitotic activity of ductal cylindric cells and
stimulates the growth of connective tissue (Porter, 1974).
The lobular units of terminal ducts of breast tissue of
young women are highly responsive to estrogen and it
exerts histamine-like effects on the microcirculation of the
breast. The density of estrogen receptors in breast tissue is
highest in the follicular phase of the menstrual cycle and
falls after ovulation. In postmenopausal women with
breast cancer, the tumor concentration of estradiol is high
because of in situ aromatization and low serum estradiol
concentrations. The ovarian estrogen hormone has a
primary role in the establishment and maintenance of
reproductive function. Additional functions of estrogen are
in the skeleton development, cardiovascular system and
brain (Mcdonnell et al, 2001).
IV. Metabolisms
Estrogens are meeflora and subsequent reabsorption
of the estrogen results in an enterohepatic circulation.
Estrogens are also metabolized by hydroxylation and
subsequent methylation to form catechol and
methoxylated estrogens (Osewa et al, 1993).
Hydroxylation of estrogens yields 2-hydroxyestrogens, 4hydroxyestrogens and 16 a-hydroxy estrogens (catechol
estrogens), among which 4-hydroxyestrones and 16a hydroxy estradiols are considered as carcinogenic.
Methylation of the 2- and 4-hydroxyestrogens by catechol
O-methyltransferase yields methoxylated estrogen
metabolites (Grubber and Hubber, 2001). Catechol
estrogens are bound to estrogen receptors and have weak
estrogenic activity in animals. Lipoidal estrogens are fatty
esters of estrogens that comprise of a separate class of
steroid hormones and they are synthesized in blood,
circulated and bind to lipoproteins. Overall, less than 10
percent of serum estradiol is associated with lipoproteins,
mainly high-density lipoproteins, but serum estradiol can
be transferred to low-density lipoproteins (Tang et al,
1997). Lipoidal estrogens are more resistant to catabolism
than free estrogens are therefore it takes lifetime to clean
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Figure 3. Blocking of estrogen receptors (Tamoxifen & Raloxifene). SERM: Selective estrogen receptor modulators.
X. Raloxifene
Raloxifene is a second generation of selective
estrogen-receptor modulators (SERM) and it was initially
developed for breast cancer. Later, it was treated as an
alternative to hormone replacement therapy for treatment
of osteoporosis. Raloxifene is a benzothiophene derivative
with a distinctly different structure from tamoxifen
(Buzdar et al, 1998). Although, raloxifene has similar
activity to tamoxifen in breast and bone it is devoid of
agonist activity in the endometrium (Riggs et al, 2003).
Raloxifene is reduces the incidence of breast cancer by
62%, and it does not increase the endometrial proliferation
or neoplasm (Cummings et al, 1999). Raloxifene
significantly reduces the risk of invasive breast cancer in
human with positive estrogen receptor status and reduces
the risk of clinical vertebral fractures (reactive reduction
35%) but it does not reduce the non-vertebral fractures.
However, it would reduce thromboembolism (44%), fetal
stroke (49%), leg cramps, peripheral edema and
gallbladder disease in breast cancer patients (Fisher et al,
1998). The influence of raloxifene on breast cancer
incidence has been reported from several ongoing trials.
The largest randomized trial to address the issue of breast
cancer risk is with raloxifene therapy. In the Multiple
Outcomes of Raloxifene Evaluation (MORE) study, 7,705
postmenopausal women existing with osteoporosis were
randomized to receive either raloxifene at 60 or 120 mg/d
or placebo. Breast cancer was monitored in the MORE
study and initial reports showed 70% reduction in the
incidence of invasive breast cancer with raloxifene
treatment compared with placebo. Raloxifene reduced the
incidence of estrogen receptor-positive breast cancers and
did not reduce the estrogen receptor-negative cancers
(Cummings et al, 1999; Ettinger et al, 1999). Raloxifene
increases the BMD and it may lower the fracture risk in
human. Raloxifene is not associated with endometrial
proliferation, but clear information on raloxifenes effect
on endometrial cancer development is not yet available
(Barrett et al, 2006).
XI. Estrogen
(Aromatase)
Synthesis
Inhibitors
XII.
Estrogen
receptor
regulators (Fulvestrant)
down
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Fulvestrant has notable efficacy in tamoxifenrefractory disease and it has demonstrated an equivalent or
superior activity than anastrozole in the metastatic cancers.
There has been recent debate existing in the dosing of
fulvestrant in humans. The published pharmacokinetic
data suggested that, once in a month of intra muscular
injection of fulvestrant at the dose rate of 250 mg provides
an adequate dose in the circulation, but it does not reach
the steady-state level quickly. Further exploration of
dosing of250 mg once in 2 weeks will reach a steady state
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XIII. Conclusion
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