Cancer Therapy Vol 6, page 655

Cancer Therapy Vol 6, 655-664, 2008

Antiestrogen therapy for Breast Cancer: An

overview
Review Article

Kishor S Kumar, Mahesh M.J Kumar*

Centre for Cellular and Molecular Biology, Hyderabad, India

__________________________________________________________________________________
*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

function. This paper will review the therapeutic methods

available for anti hormonal therapy, estrogen synthesis,
function, and metabolism and molecular mechanism of
action of anti hormonal agents

Breast cancer is the leading malignancy in women,

accounting for more than 3, 50,000 deaths per year
worldwide (Ferlay et al, 2000). Estrogens play role in
luminal mammary epithelial cell proliferation and
development of mammary cancers. About 70% of human
breast cancer is expressing estrogen receptors (Lacroxia
and Leclercq, 2004). The mammary cancers are classified
on the basis of growth requirement as estrogen dependent
and estrogen independent tumor (Stoll, 1969; Furth, 1975).
The relationship between estrogen receptor
expression and cellular responsiveness to estrogen and
antiestrogen has been extensively studied in cell lines
(Katzenellen et al, 1987), animal models (Milholland et al,
1979) and humans (Rose, 1980) and its makes ER is one
of the most important therapeutic targets in breast cancer
(Sunderland and Osborne, 1991). ER is a transcription
factor that regulates the genetic program of cell cycle
progression and growth in mammary glands. ER alpha is
considered as the primary receptor for mammary tumor
development. Antiestrogenic therapy, blocks the ability of
the estrogen and control the growth of breast cancer cells.
It is very effective treatment against ER dependent breast
cancers. Antiestrogenic treatments are blocking estrogen
receptor by selective modulators (tamoxifen and
raloxifene), destabilization and degradation of estrogen
receptor by selective down regulators (fluvestrant) and
inhibiting the estrogen synthesis (aromatase inhibitors anastozole, leterozol) -result in substantial decreases of
tumour progression and growth of patients (Wolmark and
Dunn, 2001). Recent genetic, biochemical and
pharmacological dissection of the estrogen signal
transduction pathway has led to the identification of
numerous proteins and processes that impinge on ER

II. Estrogen and Breast cancer

Estrogen is one of the major risk factor of breast
cancer progression and development. Over, 85% of the
mammary cancers in women originated from the luminal
mammary epithelial cells. Adenocarcinogenesis are
classified according to their growth requirements for
proliferation has been either hormone dependent or
hormone independent tumors (Nandi et al, 1995). Various
studies of breast cancer have reported to an increased risk
associated with elevated blood levels of endogenous
estrogen. The influence of serum estrogen concentration is
associated with the menstrual cycle in premenopausal
women and more stable concentration in postmenopausal
women. (Mark Clemons and Goss, 2001). In animal
experiment, estrogen is lead to development of mammary
tumors (Mahesh K et al, 2007) and the mechanisms of
estrogen are contributed to each phase of the
adenocarcinogenesis process of ignition, promotion and
progression.

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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Kumar and Kumar: Antiestrogen therapy for Breast Cancer: An overview

Both cytochrome CYP17 (P450 17 hyderoxylase)
and cytochrome CYP19 (P450 aromatase) are involved in
estrogen biosynthesis (Haimen et al, 1999). Aromatization
is the last step in estrogen formation and the P450
aromatare monoxygenase enzyme complex is present in
the smooth endoplasmic reticulum and functions as a
demethylase catalyst in this reaction. In three consecutive
hydroxylation reactions, estrone (E1) and estradiol (E2)
are formed from their obligatory precursors
androstenedione and testosterone respectively.

in the circulation. Lipoidal estrogens lower the

concentration of estradiol to inhibit the oxidation of lowdensity lipoproteins reported in invitro system (Shwaery et
al, 1997).

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

Figure 1. Three different types of

estrogen.

2002). The ER is a ligand-dependent transcription factor

which accounts for the latency of most estrogenic
responses in target tissues (Means et al, 1972). Estrogen
diffuses into the cell and it binds to the ligand-binding
domain of the receptor. The complex of estrogen and
estrogen receptor diffuses into the cell nucleus and these
estrogens-estrogen receptor complexes bind to specific
sequences of DNA called estrogen-response elements
(EREs). The estrogen-estrogen receptor complexes are
bound not only to the response elements but also to

VI. Molecular actions of estrogen

The molecular mechanism of estrogen on nuclear DNA
involves (Figure 2) estrogen and its nuclear receptors
complex are bound to the regulatory regions of estrogenresponsive genes as dimers and also these binding is
associated with basal transcription factors, co activators
and co repressors to alter the gene expression (Levin,

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nuclear-receptor co-activators or repressors. Estrogen
regulates the transcription of genes that lack functional
estrogen-response elements by modulating the activity of
other transcription factors and also it can enhance breast
cancer cell survival and tumor growth (Donald et al,
2002).

There are two subtypes of estrogen receptor and

several isoforms and splice variants of each subtype was
reported. The first subtype estrogen receptor , was cloned
in 1986 and the second subtype of estrogen receptor is
present in several nonclassic target tissues including the
kidney, intestinal mucosa, lung parenchyma, bone
marrow, bone, brain, endothelial cells and prostate gland
(Enmark et al, 1997). In contrast, estrogen receptor is

VII. Estrogen receptors

Figure 2. Molecular action of estrogen.

E: Estrogen Receptor, ERE: estrogen responsible elements, P450 Scc: P450 side chain cleavage enzyme, CYP17: 17-hydroxylase, 3HDS: denotes 3-hydroxysteroid dehydrogonase, DHEA: dehydroepiandrosterone, 17-KSR: 17-ketosteroid reductase, 17-HDS: 17
hydroxysteroid dehydrogonase.

found mostly in endometrium, breast-cancer cells and

ovarian stroma. The development and growth of breast
cancer is mediated through a balance of ER alpha and ER
beta molecules. Estrogen receptor and are members of
nuclear hormone receptor super family, which has
approximately 150 recognized members. Estrogen
receptors have several functional domains. ER and ER
have 96% amino-acid identity in their DNA-binding
domains, whereas there is only 53% homology in their
ligand-binding domains.These receptors differ in their
activation domains suggesting that, they may recruit
different proteins to the transcription complexes and

thereby altering the specificity of their genomic

transcriptional effects (Pettersson and Gustafsson, 2001).
The ligand-binding domain contains different sets of
amino acids that bind to different ligands and this domain
also interacts with co-regulatory proteins. The N-terminal
domain a high degree of variability and normally it
contains a transactivation domain that can interact directly
with factors of the transcriptional machinery. The Cterminal domain has contributes to the transactivation
capacity of the receptor. The DNA-binding domains of
estrogen receptors and are very similar and overall
degrees of homology of the receptors are low in cells. The

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estrogen signal transduction pathway has led to
identification of numerous proteins that impinge on ER
function (Kuiper et al, 1996; Donald et al, 2002). ER is
sequestered into target cell nuclei of large inhibitory heat
shock protein complex. which enables the displacement of
heat shock proteins and also facilitates the interaction of a
receptor dimer within the regulatory regions of target
genes. The interaction of ER with target gene promoters
can occur either directly through specific estrogen
response elements (EREs) or indirectly through contacts
with other DNA bound transcription factors such as AP1,
SP1 or NF-B. Once bound to DNA, the receptor can
either positively or negatively regulate the target gene
transcription (Donald et al, 2002). Cross talk between the
genomic and second-messenger pathways probably has
important roles in estrogenic control of cell proliferation
and inhibition of apoptosis and may have implications for
therapy (Levin, 2003). Catechol estrogen metabolites may
participate in the regulation of pathways of gene
expression or signaling or both through the estrogen
receptor. The receptor is modulated to enhance or suppress
gene activation in different target tissues (Anstead et al,
1997). One proposed mechanism is the balance of corepressor or co-activator proteins that can bind to the
SERM-ER protein complex to switch off (co repressor) or
switch on (co activator) the transcriptional potential of the
complex. However, a thorough investigation is required
for all the interacting signaling pathways mediated through
the estrogen receptor and growth factors such as epidermal
growth factor and insulin- like growth factor 1, that
function in human breast tissue normal and tumor cells.
This could facilitate the goal of achieving a
comprehensive understanding of control of proliferation
and apoptosis by estrogen and its metabolites on cancer
cells and it is perhaps a new targets for combined
therapeutic intervention. Ligand-dependent activation of
estrogen receptors have unattached to its ligand and
loosely bound to its cytoplasmic or nuclear location, but
they have attached to receptor-associated proteins. These
proteins have served as chaperones and they stabilize the
receptor in an un-activated state or mask the DNA binding
domain of the receptor. Other receptor-associated proteins
may contribute to cross talk between different signal
pathways. The specific domain within ER is required for
ligand binding, dimerization, DNA binding, and
transactivation (McDonnell, 1999). ER also plays a role
in negative regulation of ER . In response to estrodial,
ER can activate the same genes as regulated by ER .
However, ER function is to inhibiting ER

transcriptional activity in cells in which both receptors are

expressed (Hall and McDonnell, 1999). The BRCA1 gene
account for 40% to 50% of hereditary breast cancer.
BRCA1 inhibit the signaling pathway by ligand activated
estrogen receptor (ER ) through the estrogen responsive
element and also block the transcription activation
function of AF-2 of ER a (Fan et al, 1999).

VIII. Antiestrogen therapy

In 1882, Thomas William Nunn recognized
importance of ovarian functions in breast cancer growth.
In 1989, Albert Schizinger proposed surgical
oophorectomy to treat breast cancer. 37% of patients had a
tumor response with oophorectomy was reported earlier
(Beatson, 1896). Ovarian hormone of estrus and the
hormones from the ovarian tissues were investigated and
named as estrogens (Allen and Doisy, 1923). Estradiol
have synthesized and injected into immature female rats to
determine the site of actions (Jennsen and Jacbson, 1962).
The ER was isolated from ovary and characterized in
1967. Mechanism of Antiestrogenic therapy exists in three
pathways. 1. Blocking the estrogen receptors (Tamoxifen
& Raloxifene) 2. Estrogen synthesis inhibitors
(Aromatase) 3. Estrogen receptors down regulators
(Fulvestrant)

IX. Blocking of estrogen receptors

(Tamoxifen & Raloxifene)
Tamoxifen is acting an antiestrogen by inhibiting the
binding of estrogen-to-estrogen receptors. The Food and
Drug Administration has approved Toamoxifen in 1977
for the treatment of women with advanced breast cancer
(Jordan, 1999, 1995). The compound was administered to
patients as trans-tamoxifen (as the citrate salt) because this
isomer has higher affinity for estrogen receptors than cisisomer (Langan et al, 1994). Drugs such as tamoxifen are
more properly referred to as selective estrogen-receptor
modulators (SERM) because of their multiple activities. It
has estrogen-antagonist activity in breast tissue accounting
for its ability to inhibit tumor growth (Horwitz et al, 1996)
(Figure 3). Tamoxifen is absorbed readily after oral
administration and the usual dosage is 20 mg per day and
the serum half-lives of tamoxifen and its major
metabolites range from 7 to 14 days (Buckley et al, 1989;
Sunderland and Osbrne, 1991; Langan et al, 1994). In
long-term treatment, the concentrations of tamoxifen and
its metabolites in serum remain constant for as long as 10
years and its reduced bioavailability is not a cause for

Figure 3. Blocking of estrogen receptors (Tamoxifen & Raloxifene). SERM: Selective estrogen receptor modulators.

acquired resistance. Tamoxifen can be detected in serum

for several weeks and in tumor tissue for several months
after the treatment is discontinued (Lien et al, 1991). The
anti tumor effects of tamoxifen are thought to be due to its

anti estrogenic activity mediated by competitive inhibition

of estrogen binding to estrogen receptors (Osborne et al,
1996). As a consequence, tamoxifen inhibits the
expression of estrogen-regulated genes including growth
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factors and angiogenic factors secreted by the tumor that
may stimulate the growth by autocrine or paracrine
mechanisms. The net result is blocking the G1 phase of the
cell cycle and a slowing of cell proliferation. Tumors may
regress because of this altered balance between cell
proliferation and ongoing cell loss. Tamoxifen directly
induces programmed cell death in tumour tissues (Ellis et
al, 1997) and it reduces the risk of recurrence and death
from breast cancer and also it provides effective palliation
for patients with metastatic breast cancer. Therefore it is
useful to treat the women who have estrogen-receptorpositive invasive breast cancer. An exception might be on
the basis of prognostic factors such as an invasive or
tubular mucinous or papillary tumor with negative axillary
nodes - to have a very low risk of disseminated disease.
Tamoxifen is an initial hormonal therapy of choice for
postmenopausal women with metastatic breast cancer and
it is used as first- or second-line therapy in younger
women. It is safe and well tolerated, but the risk of
endometrial cancer is high.

glandular tissues including subcutaneous fat, liver, muscle,

brain, normal breast, and breast-cancer tissue (Miller et al,
1982). Peripheral aromatase activity and plasma estrogen
levels are correlated with body-mass index in
postmenopausal women. The concentration of estradiol in
breast-carcinoma tissue is approximately 10 times higher
than the concentration in plasma (Longcope et al, 1986).
The level of estrogen is high in breast cancer patient and
estrogen sends a growth signal to ER following which
uncontrolled proliferation of cells occur. Aromatase
inhibitors block the estrogen signaling that leads to fewer
growth signals to ER and hence cancer growth can be
slowed down or stopped.
Aromatase inhibitors inhibit several cytochrome P450 enzymes involved in adrenal steroidogenesis and these
are redeveloped for use as medical adrenalectomy
against advanced breast cancer (Santen et al, 1977). They
are described as first-, second- and third-generation
inhibitors according to the chronological order of their
clinical development and they are further classified as type
1 type 2 inhibitors (Figure 4) according to their
mechanism of action.
Type 1 inhibitors are steroidal analogues of
androstenedione and they bind to the same site on the
aromatase molecule. Type I inhibitors, unlike
androstenedione, bind irreversibly to aromatase and gets
converted to reaction intermediates. Therefore, they are
commonly known as enzyme in activators. Type 2
inhibitors are non steroidal and bind reversibly to the heme
group of the enzyme by basic nitrogen atom. Anastrozole
and letrozole are third-generation inhibitors and they bind
at their triazole groups. Anastrozole, letrozole and
exemestane are administered orally to the breast cancer
patients (Steele et al, 1987). Type-I compound and a typeII compound have clinical efficacy, but the disadvantage
of intramuscular injections are required to deliver the
molecules. (Lonning et al, 1991; Wisemen and Adkins,
1998). Aminoglutethimide induces cytochrome P-450
activity, but it reduces tamoxifen levels (Lien et al, 1990).
The third-generation aromatase inhibitors have been found
in pre clinical studies to be more potent than
aminoglutethimide. All of them markedly suppress the
plasma estrogen levels in postmenopausal women. Clinical
doses of anastrozole, exemestane and letrozole are greater
than 97 percent (Geisler et al, 1998) as compared with
aminoglutethimide (MacNeill, 1992). Letrozole was
associated with greater aromatase inhibition than
anastrozole and lower the plasma levels of estrone and
estrone sulfate (Geisler et al, 2002). Aromatase has intra
tumoral activity in the majority of breast carcinomas and
isotopic assays shown that such activity contributes to
decrease the plasma estrogen levels. Anastrozole, letrozole
and exemestane are markedly inhibiting the breast cancer
(Miller and Dixon, 2001). Overall trials shown that
aromatase inhibitors are favorable to tamoxifen in post
menopausal ER positive patients, secondary to decreased
recurrence and a decrease in undesirable side effects of
endometrial cancer and venous thrombosis. The
disadvantage with aromatase inhibitors is the higher rate
of osteoporosis and subsequent fracture as well as higher
cholesterol levels.

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)

Aromatase inhibitors are markedly suppressing the

plasma estrogen levels in postmenopausal women by
inhibiting or inactivating aromatase, the enzyme
responsible for synthesis of estrogens from androgenic
substrates. Aromatase is an enzyme of cytochrome P-450
super family and the product of the CYP19 gene (Evans et
al, 1986) and it is present at lower levels in several non

down

Fulvestrant is the selective estrogen receptor down

regulator and FDA has recently approved it for use in
advanced breast cancer and metastatic cancer (Howell,
2001). The agonist properties of tamoxifen and other
SERMs can contribute to an increased risk of endometrial
carcinoma and the development of resistance in tumor

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Kumar and Kumar: Antiestrogen therapy for Breast Cancer: An overview

cells. Fulvestrant is a 7-alkyl analog of estradiol having a
unique mechanism of action when compared with
tamoxifen and other SERMs. Tamoxifen binds to the ER
results in dissociation of heat shock proteins,
homodimerization and inhibition of transactivation in
breast tissue. Fulvestrant acts quite differently binding to
ER and causes dissociation of heat shock proteins.

However, the bulky side chain of fulvestrant prevents

dimerization and results in degradation of ER. The result
is not only inhibition of ER activity but also a dramatic
decline in ER expression levels (Howell, 2001). As a
result of down regulatory activity, fulvestrant has been
termed a SERD (Figure 5).

Figure 4. Estrogen Synthesis Inhibitors (Aromatase).

Figure 5. Estrogen receptor
down regulators or selective
estrogen receptor down regulator
(SERD).

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

more rapidly in the circulation (Howell et al, 2002). The

main adverse effects of fulvestrant are nausea, vomition,
constipation and diarrhea. Interestingly, fulvestrant does
not cross the blood-brain barrier and it seems to cause less
menopausal symptoms than other antiestrogens (Howell et
al, 1995). It does not induce endometrial thickening, but
longer follow-up of the larger clinical trials would be
required to assess its effects on endometrial cancer risk
(Figure 6).

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Figure 6. Molecular mechanism of action of anti estrogenic therapy.

XIII. Conclusion

preventive and therapeutic intervention that block estrogen

receptor function or drastically reduce the levels of
endogenous estrogen through inhibition of its synthesis.
The development of additional strategies on the basis of
the inhibition of estrogen metabolism, inactivation of
reactive quinolones, silencing of estrogen receptors genes
and specific inhibition of membrane estrogen-receptor
activated second messenger pathways will probably lead
to the availability of additional effective approaches.
However, thorough investigation is required for all the
interacting signaling pathways mediated through the
estrogen receptor and growth factors, such as epidermal
growth factor and insulin- like growth factor 1, that
function in human breast tissue, normal and tumor cells.

Current anti estrogen receptor strategies include

blocking by selective modulators (Tamoxifen and
Raloxifene), destabilization and degradation of estrogen
receptor by selective down regulator (fulvestrant) and
disruption of estrogen synthesis (aromatase inhibitors such
as anastrole, letrozole or exemestane), any of which alone
can result in a substantial decrease of tumor growth of
estrogen receptor positive patients. Resistance to therapy
is most often observed during the treatment of advanced
breast cancer. Currently, several clinical trials indicated
that aromatase inhibitors should be used for hormonal
therapy and also it is superior for prevention of recurrence.
Treatment for recurrent cancer could be tailored for
individual patient based on disease characteristics and
other side effects such as osteopenia, cardiac risk, venous
thrombosis and uterine cancer. The third generation
aromatase inhibitor (anastrole, letrozole) is a new
development in the endocrine treatment of estrogen
receptor positive breast cancer in post menopausal woman.
In advanced disease, letrozole is convincingly better than
tamoxifen, but long-term effects of profound estrogen
suppression in postmenopausal woman are unknown.Role
of estrogen in breast cancer led to development of new

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