Radiol Oncol 2002; 36(1): 63-72. 

review 


Environment and breast cancer – the role of xenooestrogens 


in breast cancer carcinogenesis 

Andrej Plesničar1, Branko Družina2, Viljem Kovač3, Božo Kralj1 

1University College of Health Care, 2Institute of Public Health, 3Institute of Oncology, 
Ljubljana, Slovenia 

Background. The survival rate of breast cancer patients has not changed much in the last few decades in 
developed countries. In order to improve the efficacy of breast cancer prevention and treatment, the role of 
xenooestrogens in the mechanisms of its development has been evaluated. These industrial chemicals bear 
little structural resemblance to each other and bind to the oestrogen receptors of exposed cells and/or trigger 
oestrogenic responses in laboratory test systems. Exposure to xenooestrogens has been regarded as a risk 
factor for carcinogenesis and a preventable cause of breast carcinoma. Several epidemiological and experimental 
studies in in vivo and in in vitro conditions of the influence of xenooestrogens on the occurrence of 
breast cancer have been conducted in the last decades and have shown ambiguous results. 
Conclusions. No increase in breast carcinoma incidence could be found in women who were exposed to relatively 
high concentrations of xenooestrogens for extended periods and small quantities of these compounds 
that are present in the environment probably cannot act as etiological agents for the occurrence of this disease. 
A multi step approach is suggested regarding the sequence of studies and measures that should be taken 
to further assess the importance of xenooestrogens on breast cancer carcinogenesis. 

Key words: breast cancer; xenooestrogens; carcinogenesis 

Received 16 November 2001 
Accepted 4 December 2001 

Correspondence to: Andrej Plesničar, MD, MSc, University 
College of Health Care, Poljanska c. 26a, SI 
1000 Ljubljana, Slovenia; Phone: +386 1 300 11 67; E-
mail: andrej.plesnicar@vsz.uni-lj.si 

Introduction 

The word cancer is used to describe several 
diseases that are caused by multiple genetic 
changes in the cells of different tissues. These 
changes may only manifest themselves after 
several years, causing the proliferation 
and immortalisation of affected cells. The clinical 
consequences of these changes are specific 
clinical states which lead to the premature 
death of 25-30 % of the population.1 The 
improvement of survival in cancer, particularly 
breast cancer, the survival rate of which 


Plesničar A et al. / Xenooestrogens and breast cancer 

has not changed significantly in the last few 
decades in the developed countries, is thus 
among the declared goals that were set to improve 
the health of the whole population by 
the year 2000.2 The relative five-year survival 
rate of breast cancer patients in the United 
States (US) was practically constant at slightly 
less than 80 % for the 1974-1987 period.1 
The relative five-year survival rate for the patients 
with this disease who were diagnosed 
in the 1977-1985 period in Southern Australia 
was 72.8 %; however, patients who had breast 
cancer diagnosed there in the consequent 
1986-1994 period had only slightly improved 
survival rate of 78 %.3 In order to further improve 
the efficacy of breast cancer prevention 
and treatment, conditions and mechanisms 
that lead to its development must be known. 
An especially critical assessment of the significance 
of and role played by environmental 
risk factors is therefore necessary. According 
to some sources, xenooestrogens, industrial 
chemicals that bear little structural resemblance 
to each other and that bind to the oestrogen 
receptors (ER) of exposed cells 
and/or trigger oestrogenic responses in laboratory 
test systems, are among these factors.4 

Xenooestrogens and breast cancer 

Breast cancer: some characteristics 

By definition, breast cancer is a disease in the 
course of which malignant proliferation of 
the epithelial cells in lobules and ducts of the 
breast tissue takes place.5 However, this definition 
could be regarded as too limited since 
breast cancer is a field researched by experts 
that are not necessarily specialised in cell and 
tissue pathology. Breast cancer is the second 
most frequent form of cancer affecting women, 
non-melanocytic skin cancer being the 
most frequent.6 It is also the most common 
cause of death for female cancer patients,7 
the incidence of which is up to five times higher 
in first-world countries than in some less 

developed Asian and African countries.8 Moreover, 
the incidence of breast cancer in first-
world countries still seems to be rising slow


ly.1,9 

Histologically, breast cancer is usually a 
carcinoma that develops in the terminal ductal-
lobular units. In most cases, a breast carcinoma 
develops from ductal cells and less frequently 
from lobular cells, whereas tumour 
formations that can be histologically classified 
as primary sarcoma, lymphoma or unclassified 
tumours are relatively rare, as are metastatic 
breast tumours that originate from 
other organs.5,10-12 The occurrence and rapid 
development of breast carcinoma and the associated 
incidence of this disease in women is 
connected to the presence of certain risk factors. 
They include a relatively low age at first 
menstruation and a relatively high age at menopause, 
a high age at first birth, obesity and 
a fat-rich diet, excessive alcohol consumption, 
and benign breast disease and breast carcinoma 
in the family’s medical history. The 
importance of oral contraception and postmenopausal 
hormone therapy for the occurrence 
and development of this disease is not 
yet completely clear.1,5,11 Unfortunately, al-

Table 1. Characteristics of patients with symptomatic 
breast carcinoma at the time of diagnosis 

1. The most common symptom among diagnosed 
breast carcinoma patients is a lump (present in 
90 % of cases that exhibit symptoms at time of 
diagnosis), discovered by the patient during self 
examination, showering or bathing. 
2. Pain is present in 10 % of breast carcinoma patients. 
3. Skin-colour change on the skin of the affected 
breast, nodules or oedema (peau d’orange) are 
present in 5-10 % of breast carcinoma patients. 
4. Changes on nipples are apparent in 5 % of patients, 
half of which have also exhibited discharge 
from the breast; with the other half, retraction or 
eczematoid changes can be observed. 
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Plesničar A et al. / Xenooestrogens and breast cancer 

most 80% of breast carcinoma patients only 
visit a doctor for the necessary diagnostic 
procedures after the symptoms and signs of 
the disease become apparent (Table 1).5,9,11 

Xenooestrogens and breast carcinoma 
carcinogenesis 

According to several experts in this field, the 
increase in breast cancer incidence in recent 
decades appears to be caused by prolonged 
exposure to oestrogens. It is a well-known 
fact that the incidence of breast carcinoma in 
developed countries has risen the most in the 
population of post-menopausal women.4,13,14 
Moreover, prolonged exposure to environmental 
oestrogens is probably a significant 
risk factor that contributes to the higher incidence 
of breast cancer in the US compared 
with the countries of East Asia. The importance 
of prolonged exposure to oestrogens in 
connection with cancer can be shown by the 
fact that, in the US, first menstruation occurs 
at the average age of 12.8 years whereas in 
China it occurs at the average age of 17 years.
4 Also noteworthy is the fact that the incidence 
of breast cancer in immigrants from 
East Asia and their descendants is practically 
the same as with women who were born in 
the US along with several generations of their 
ancestors.15,16 Davis et al. set up a hypothesis 
in 1993 according to which xenooestrogens 
could be a risk factor for the 
carcinogenesis of breast carcinoma in women 
and that prolonged exposure to these compounds 
could be considered one of the preventable 
causes of this disease.4,17 In the last few 
years, several structurally different xenooestrogens 
have been discovered which can, 
due to their tertiary structure and conformation, 
bind to oestrogenic receptors (ER) or induce 
oestrogenic responses in laboratory test 
systems, or can function using both mechanisms 
at the same time.18-20 Among xenooestrogens 
are the halogenated organic compounds 
that were used until recently as 

pesticides. Some better known examples are 
kepone, toxaphene, endosulfan, dieldrin, o,p’DDT, 
p,p’-DDE, some polychlorinated biphenyl 
(PCB) mixtures, hydroxy-PCB, nonlyphenol 
and some phthalates.4 

Epidemiological studies of importance of 
xenooestrogens for breast cancer carcinogenesis 

Epidemiological research into the importance 
of xenooestrogens for breast cancer carcinogenesis 
represents only a part of research on 
the environmental risk factors that may influence 
the occurrence and development of this 
disease, and this is despite a rising awareness 
of their importance.21 The studies conducted 
have mostly been case-control studies and investigated 
the presence of organic halogenides, 
i.e. xenooestrogens in breast carcinoma 
patients compared to healthy control subjects. 

The hypothesis that claims xenooestrogens 
are a risk factor for breast cancer formation 
and development has been confirmed by some 
studies but disproved by others.22-28 According 
to some earlier studies, no difference 
was observed in PCB and DDE concentrations 
in the breast tissues of patients and control 
subjects. However, PCB concentrations 
in necropsy samples of breast carcinoma patients 
were higher than in the necropsy samples 
of control subjects.22,23 A study published 
in 1992 by Falck et al. showed that PCB 
and DDE concentrations in breast carcinoma 
patients’ breast tissue were higher than concentrations 
in healthy control subjects.24 A similar 
study published later by Dewailly et al. 
only found higher DDE concentrations in breast 
tissue. Some groups of breast carcinoma 
patients had increased serum concentrations 
of DDE and PCB compared to healthy control 
subjects,25 whereas an extensive study published 
in 1994 by Krieger et al. failed to confirm 
these differences.27 In one of the extensive 
studies that followed, Henderson et al. 
found a large increase in the serum concentrations 
of polybrominated biphenyls (PBB) 

Radiol Oncol 2002; 36(1): 63-72. 


Plesničar A et al. / Xenooestrogens and breast cancer 

in breast carcinoma patients compared to the 
control subjects.28 

These epidemiological studies were unable 
to define the importance of xenooestrogens 
for the carcinogenesis of breast carcinoma, as 
higher serum concentrations of chlorinated 
organic compounds may have been, in some 
studies, caused by specific eating habits, since 
increased concentrations of these compounds 
were found in high-fat food as well as 
fish.4 It should be noted, however, that the results 
of these and similar studies have in 
many cases led the laboratory scientists to seek 
to elucidate the role of xenooestrogens in 
the mechanisms of the breast cancer carcinogenesis. 


Studying the importance of xenooestrogens 
for breast cancer carcinogenesis in experimental 
in vitro conditions 

Several xenooestrogens that are able to bind 
to ER (Table 2) have been identified in the last 
few years using cell cultures in experimental 
in vitro conditions.4,18-20 By binding to ER, the 
xenooestrogens could act as sex hormones 
and accelerate breast carcinoma cell proliferation. 
In this mitogenic effect, ER play the role 
of genetic transcription factors that release 
the block in the G1 phase of the cell cycle.1 

Other mechanisms of the effects xenooestrogens 
have on breast carcinoma cells have 

Table 2. Xenooestrogens that bind to oestrogenic receptors 
(ER) (in vitro cell cultures) 

Toxaphene 
Endosulphan 
Dieldrin 
o,p’-DDT 
p,p’-DDE 
PCB (mixtures and PCB-like compounds) 
Hydroxy-PCB 
Bisphenol-A 
Nonylphenol 
Phthalates 

also been researched with the help of in vitro 
conditions. The results of some studies indicate 
that the xenooestrogens reduce the enzymatic 
activity of 17ß-estradiol 2-hydroxylase, 
and increase the enzymatic activity of E2 
16.-hydroxylase, which leads to a change in 
the ratio of the two respective metabolites in 
the cell. After exposure to oestrogens, the 
concentration of 16.-hydroxyoestrone in the 
cells is increased and is higher than the concentration 
of 2-hydroxyestrone, which is why 
the ratio of their concentrations is increa


sed.17,29 

Previous studies also indicate the 
importance of the change of the ratio which 
showed that E2 16.-hydroxylase acts as a 
strong oestrogen whereas 17ß-estradiol 2hydroxylase 
is a partial antagonist of the ER 
receptors.30,31 In the MCF-7 breast carcinoma 
cell line, many xenooestrogens (Table 3) have 
the aforementioned effect on the two hydroxylases,
32 whereas the indole-3-carbinole 
(I3C), an ingredient of several vegetables, inhibits 
the development and growth of breast 
carcinoma in in vitro as well as in vivo models.
33,34 However, later studies have shown 
that a change in activity of E2 2-hydroxylase 
in MCF-7 cells is not caused by inducing the 
P 450 system but is instead a result of this 
system’s direct interactions with various chemical 
substrates. Moreover, E2 2-hydroxylase 
activity was reduced after adding pure antioestrogen 
ICI 164,384. These results show that 

Table 3. Xenooestrogens that reduce the enzymatic activity 
of 17-estradiole 2-hydroxylase and increase the 
enzymatic activity of 16-hydroxylase (in vitro cell cultures: 
MCF-7 cells) 

Endosulphan 
Kepone 
p,p’-DDE 
o,p’-DDE 
o,p’-DDT 
Atrazine 
2,2’,4,4’,5 pentachlorobiphenyl 
7,12-DMBA 

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Plesničar A et al. / Xenooestrogens and breast cancer 

modulation of E2 2-hydroxylase activity in 
MCF-7 cells cannot serve as a reliable test for 
carcinogenic effects of oestrogenic pesticides 
and other compounds that are thought to 
promote the occurrence and development of 
breast carcinoma.4 

Studying the importance of halogenated organic 
compounds in the development of breast 
carcinoma in experimental in vivo conditions 

Some studies of the importance of halogenated 
organic compounds and related xenooestrogens 
in the occurrence and development 
of breast carcinoma were conducted using in 
vivo experimental models with animals (Table 
4). Adding atrazine to Sprague-Dawley laboratory 
rats decreased the latent period of 
breast cancer development;29 a similar study 
with Fisher laboratory rats showed no changes.
35 The results of the study on the Fisher 
laboratory rats also indicated that atrazine 
and related compounds influence the oestrus 
and regulation of synthesis of the luteinising 
hormone via non-oestrogenic pathways.35 
Additional studies showed that atrazine and 
simazine have no oestrogenic effect,36 while a 
study done previously found that DDT caused 
an increase in breast cancer incidence in 
male Sprague-Dawley rats that were given 
acetamidophenantrene at the same time.37 
However, a much earlier study showed that 

DDT reduces the incidence of breast tumours 
induced by dimethylbenzanthracene (DMBA).
38 A review of these studies and examinations 
cannot prove the validity of the hypothesis 
of the important role of xenooestrogens 
in breast carcinoma carcinogenesis, as 
some halogenated organic compounds and 
xenooestrogens can both inhibit and accelerate 
it in in vivo conditions. 

Halogenated organic compounds 
with antioestrogenic activity 

Several of the numerous studies on the importance 
of xenooestrogens for carcinogenesis 
and the development of breast carcinoma 
found that there were some halogenated organic 
pollutants whose effects were directly 
opposite to those of oestrogens. One such antioestrogenic 
compound is 2,3,7,8-tetrachlorodibenzo-
p-dioxine (TCDD), which according 
to some studies slows the occurrence of 
spontaneous breast and uterus tumours in female 
Sprague-Dawley rats and the occurrence 
of breast tumours in immunosupressed 
B6D2F1 mice with xenografts of the MCF-7 
cells.39-41 Additional studies confirmed the 
antioestrogen and antitumor effect of TCDD 
and some halogenated aromatic hydrocarbons 
(HAH) in human breast carcinoma cell 
lines in in vivo as well as in vitro conditions 
(Table 5).42 

Table 4. Halogenated organic compounds that play a role in breast cancer development (animal experimental models 
– in vivo) 

Compound Animal model Result Reference 

Atrazine Rats (female) A decrease in the latent period of breast 29 
(Sprague-Dawley) cancer development 
Atrazine Rats (female) (Fischer) No change in the latent period of breast 35 
cancer development 
ACTDP and DDT Rats (male) Increased breast tumour incidence 

37 
(Sprague-Dawley) 
DDT Rats (female) (Fisher) A decrease in DMBA-induced breast 28 
tumour incidence 

ACTDP = acetamidophenantrene; DMBA = dimethylbenzanthracene 

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Plesničar A et al. / Xenooestrogens and breast cancer 

Table 5. Halogenated organic compounds that act as antioestrogens (in vitro cell cultures and in vivo animal experimental 
models) 

Compound Animal model Result Reference 
TCDD Rats (female) A decrease in the occurrence 39 
(Sprague-Dawley) of spontaneous breast and uterine tumours 
TCDD Rats (female) Inhibition of breast tumour carcinogenesis 40 
(Sprague-Dawley) 
TCDD Mice (immunosupressed A decrease in the occurrence 41 
with MCF-7 xenografts) of spontaneous tumours 
TCDD and HAH Human breast cancer Lower activity of peroxydases and binding 42 
cell lines of EGRF receptors, smaller amounts 
of m-RNA 

TCDD = 2,3,7,8-tetrachlorodibenzo-p-dioxine; HAH = halogenated aromatic hydrocarbons 

TCDD acts similarly to the “pure” antioestrogen 
ICI 164,384, which binds competitively 
to ER and is an ER antagonist.43 Both 
compounds inhibit some of the oestrogenic 
responses and reduce concentrations of oestrogen-
associated proteins in MCF-7 cells. 
However, TCDD does not bind to ER or receptors 
for other steroid hormones. Like the 
various classes of HAH and polychlorinated 
aromatic hydrocarbons (PAH), it binds to the 
aryl-carbohydrate receptors that trigger signal 
pathways similar to those triggered by 
the other ligand-induced transcription factors.
4, 42 Aryl-carbohydrate receptor agonists, 
which in addition to TCDD and similar pollutants 
from the class of halogenated hydrocarbons 
also include I3C and related hetero-PAH 
found in vegetables and PAH released with 
the cooking of fish and meat,4 inhibit the 
growth-factor-induced growth of human breast 
carcinoma cells.44-45 

Various oestrogenic and antioestrogenic 
compounds in the diet 

An assessment of the influence of the dietary 
intake of xenooestrogens on breast carcinoma 
incidence should also include other compounds 
with oestrogenic and antioestrogenic effects 
that may be present in the diet. The characteristics 
of exposure to halogenated orga-

Radiol Oncol 2002; 36(1): 63-72. 

nic compounds with a weak oestrogenic effect 
are not known. However, there are estimates 
for average daily exposure to oestrogenic 
compounds in the diet according to regular 
measurements of their concentrations in 
various kinds of food. As reported by Safe 
and McDougal, the average daily intake of 
DDT, DDE, toxaphene and dieldrin is about 

2.5 micrograms per day;4 the average daily intake 
for other xenooestrogens is not known.46 
Bioflavonoids are an important dietary source 
of compounds with oestrogenic activity and 
can be found in most fruits, vegetables, walnuts 
and hazelnuts. The estimated dietary intake 
of oestrogenic bioflavonoids may reach 
up to 1000 milligrams per day. However, the 
concentrations of oestrogenic lignans in various 
kinds of foods, which have been found in 
human serum, are as yet unknown.46-48 Besides 
these xenooestrogens, the usual diet contains 
compounds with antioestrogenic effects, 
as well as compounds that reduce the probability 
of breast carcinoma occurrence with 
other mechanisms. Some of them include various 
cell antioxidants and terpenoids.4,46 
Estimates have been made of the dietary concentrations 
of other halogenated organic compounds 
with antioestrogenic effects and other 
compounds that act as aryl-carbohydrate receptor 
antagonists, such as TCDD, HAH, 
PAH, and I3C.49-51 

Plesničar A et al. / Xenooestrogens and breast cancer 

An assessment of the importance 
of xenooestrogens for breast carcinoma 
carcinogenesis 


Studies of the occurrence and development of 
breast carcinoma in the last three decades have 
implicated exposure to natural or synthetic 
oestrogens as a risk factor for the occurrence 
of breast carcinoma in women.1,4 Since 1993, 
when Davis et al. set up a detailed hypothesis 
according to which prolonged exposure to xenooestrogens 
could be considered a preventable 
cause for the occurrence of this disease in 
women, several epidemiological and experimental 
studies in in vivo as well as in vitro 
conditions have been conducted to ascertain 
the validity of this hypothesis.17 It is impossible 
to either prove or deny it even with the 
collected results of a large number of studi


es.4,17 

No increase in breast carcinoma incidence 
could be found in women who were exposed 
to relatively high concentrations of PCB and 
DDT for extended periods.52 The small quantities 
of these compounds that are present in 
the environment probably cannot act as etiological 
agents for the occurrence of this disease. 
It should also be noted when studying 
the prolonged exposure of women to xenooestrogens 
that an ordinary diet contains several 
compounds that have been shown to prevent 
the occurrence and development of 
breast carcinoma in in vivo and in vitro conditions. 
Other xenooestrogen-like pollutants, in 
addition to various cell antioxidants and terpenoids, 
have been discovered in the diet, 
such as TCDD and HAH; these have been 
shown to act as antioestrogens, unlike other 
pesticides from the class of halogenated 
hydrocarbons.4,49,53 

Also noteworthy is the fact that the intake 
of weakly oestrogenic pesticides from the 
class of halogenated hydrocarbons, whether 
in the diet or in some other way, represents 
only a minor part of daily exposure to oestrogens. 
Several women receive relatively high 

quantities of potent oestrogenic drugs either 
through hormone contraception or hormone 
replacement therapy, yet their risk of breast 
carcinoma is minimal.16 

Xenooestrogens and breast carcinoma 

– a public health perspective 
The environment we live in and depend on 
can influence our health for better or worse.21 
An increasing incidence of breast carcinoma 
has been observed in most industrially and 
agriculturally developed countries in the last 
three decades,2,5-9 the causes of which are subject 
to a large number of epidemiological 
and clinical studies, as well as studies in experimental 
in vivo and in vitro conditions. Since 
pesticides have achieved widespread use 
in this period due to intensive agricultural 
production, a study of these industrially made 
compounds as risk factors is part of these 
ongoing research projects. Some of these 
compounds are called xenooestrogens due to 
the fact that they are a part of the environment 
and because of their weakly oestrogenic 

effects.4,5,17,52-54 

The number of breast carcinoma casualties 
and their relative five-year survival rate after 
the diagnosis of the disease have not changed 
much despite advances in treating the 
symptomatic disease.1-3 Although screening 
programmes using mammography are relatively 
expensive, several randomised studies 
have shown that a well-considered application 
of these programmes reduces the mortality 
rate of breast carcinoma patients.1, 2, 10, 11 
However, since these programmes cannot lead 
to an immediate reduction in the mortality 
rate,55 it is important that the possibilities of 
improving the overall situation by applying 
primary prevention methods are taken into 
consideration. The fact that several cancer research 
and treatment institutions are conducting 
a number of studies on the efficacy of various 
pharmacological approaches to breast 

Radiol Oncol 2002; 36(1): 63-72. 


Plesničar A et al. / Xenooestrogens and breast cancer 

carcinoma prevention is also important. The 
publication of results of studies on the chemoprevention 
of this carcinoma with Tamoxiphen 
has aroused considerable professional 
and public interest.56 

A large part of the well-informed public 
shows concern about the possible influence 
environmental risk factors may have on the 
occurrence of various diseases. Part of this 
public is particularly concerned about problems 
relating to the occurrence of breast carcinoma 
and other cancerous diseases in relation 
to xenooestrogens.4 Unfortunately, the 
results of studies of the influence of xenooestrogens 
on breast cancer occurrence are ambiguous, 
which makes educating the general 
public through clear and simple data rather 
complicated. In spite of this, doctors and other 
medical professionals in the primary health 
network should help breast carcinoma patients 
and everyone else to interpret the danger 
posed by the presence of xenooestrogens in 
their environment. They should also consider 
the possibility, when conducting clinical examinations 
and examining a medical history, 
that this disease forms due to a possible prolonged 
exposure to these chemicals.1, 2 

Suggestions have been made regarding the 
sequence of studies and measures that should 
be taken to assess the importance of environmental 
risk factors. It is necessary to identify 
the compound – in this case, one or more 
xenooestrogens which, due to their presence 
in the environment, may represent a risk factor. 
Next, the time of exposure to one or more 
xenooestrogens, the number of such episodes, 
and their duration and intensity must be 
determined. The third step towards such an 
estimate is to identify the characteristics of 
acute or chronic exposure to xenooestrogens 
with regard to breast carcinoma carcinogenesis. 
Especially important is experimental 
work in laboratories. The characteristics and 
importance of the link between exposure to 
xenooestrogens and the predicted results of 
exposure must be determined. Finally, the 

risk of breast carcinoma carcinogenesis in 
every woman that has been exposed to environmental 
xenooestrogens must be defined, 
as must be the probable consequences of 
such exposure for a larger population over a 
longer time period and a calculation of population 
attributive risk, population attributive 
risk in percentages and odds ratios. By studying 
xenooestrogens’ role in breast carcinoma 
carcinogenesis, such an estimate would be 
difficult to make, since the possible effects of 
exposure to relatively small concentrations of 
these compounds in the environment and in 
the routes of entry should be taken into account. 
Despite these potential problems, it is 
necessary to obtain such estimates so they 
can be used when promoting healthy lifestyles 
and also in order to introduce and justify 
all public and individual measures that must 
be taken to remove or at least reduce the presence 
of xenooestrogens in the environment. 
A further reduction in breast carcinoma incidence, 
and consequentially mortality due to 
breast carcinoma, could thus potentially be 

achieved.1-5,11,46-50,52-54,57 

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