Impact of combinations of EGF, TGFβ, 17β-oestradiol, and inhibitors of corresponding pathways on proliferation of breast cancer cell lines
Aim: The impact of combinations of anti-cancer drugs and growth factors on tumour cells may differ from the assumed sum of the effects of each factor separately. Therefore it is important to study the effects of different combinations of various drugs and treatments. Our aim was to study the effects...
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| Cite this: | Impact of combinations of EGF, TGFβ, 17β-oestradiol, and inhibitors of corresponding pathways on proliferation of breast cancer cell lines / M. Mints, S. Souchelnytskyi // Experimental Oncology. — 2014. — Т. 36, № 2. — С. 67-71. — Бібліогр.: 20 назв. — англ. |
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| author_facet | Mints, M. Souchelnytskyi, S. |
| citation_txt | Impact of combinations of EGF, TGFβ, 17β-oestradiol, and inhibitors of corresponding pathways on proliferation of breast cancer cell lines / M. Mints, S. Souchelnytskyi // Experimental Oncology. — 2014. — Т. 36, № 2. — С. 67-71. — Бібліогр.: 20 назв. — англ. |
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| description | Aim: The impact of combinations of anti-cancer drugs and growth factors on tumour cells may differ from the assumed sum of the effects of each factor separately. Therefore it is important to study the effects of different combinations of various drugs and treatments. Our aim was to study the effects on breast cancer cell proliferation of EGF, TGFβ and 17β-oestradiol, three important regulators of breast tumourigenesis, and their respective inhibitors in different combinations. Materials and Methods: We screened the effects on proliferation of MCF7 and MDA-MB-231 cells of ninety different combinations of EGF, TGFβ and 17β-oestradiol, Iressa, SB431542 and Tamoxifen. Meta-data analysis of available clinical data was performed to validate observed proliferation data. Results: In MDA-MB-231 cells, TGFβ1 was found inhibitory when cells were simultaneously treated with EGF and 17β-oestradiol, with the effect potentiated by addition of all inhibitors combined. In the same cells, Iressa when combined with EGF was paradoxically stimulatory. Tamoxifen inhibited MCF7 cells co-treated with EGF or oestrogen, and enhanced the inhibitory effect of TGFβ in MDA-MB-231 cells. Meta-analysis of clinical gene expression studies confirmed several of these points, showing enhanced TGFβ and EGF expression in Tamoxifen-treated patients to correlate with decreased tumour size and grade respectively, and combined TGFβ-EGF expression to decrease the risk of metastasis. Conclusion: Our study shows significant differences in proliferation response to drugs and growth factors between MCF7 cells which do not have propensity to form metastases in animal models and MDA-MB-231 cells which may form metastases upon inoculation into animals. Several of these differences are unexpected and confirmed by clinical observations. Key Words: breast cancer, combinatorial treatment, EGF, oestrogen, TGFβ.
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Experimental Oncology 36, 67–71, 2014 (June) 67
IMPACT OF COMBINATIONS OF EGF, TGFβ, 17β-OESTRADIOL,
AND INHIBITORS OF CORRESPONDING PATHWAYS
ON PROLIFERATION OF BREAST CANCER CELL LINES
M. Mints1, S. Souchelnytskyi*1, 2
1Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
2OCD-AB, Uppsala, Sweden
Aim: The impact of combinations of anti-cancer drugs and growth factors on tumour cells may differ from the assumed sum of the ef-
fects of each factor separately. Therefore it is important to study the effects of different combinations of various drugs and treat-
ments. Our aim was to study the effects on breast cancer cell proliferation of EGF, TGFβ and 17β-oestradiol, three important
regulators of breast tumourigenesis, and their respective inhibitors in different combinations. Materials and Methods: We screened
the effects on proliferation of MCF7 and MDA-MB-231 cells of ninety different combinations of EGF, TGFβ and 17β-oestradiol,
Iressa, SB431542 and Tamoxifen. Meta-data analysis of available clinical data was performed to validate observed proliferation
data. Results: In MDA-MB-231 cells, TGFβ1 was found inhibitory when cells were simultaneously treated with EGF and
17β-oestradiol, with the effect potentiated by addition of all inhibitors combined. In the same cells, Iressa when combined with
EGF was paradoxically stimulatory. Tamoxifen inhibited MCF7 cells co-treated with EGF or oestrogen, and enhanced the in-
hibitory effect of TGFβ in MDA-MB-231 cells. Meta-analysis of clinical gene expression studies confirmed several of these points,
showing enhanced TGFβ and EGF expression in Tamoxifen-treated patients to correlate with decreased tumour size and grade
respectively, and combined TGFβ-EGF expression to decrease the risk of metastasis. Conclusion: Our study shows significant
differences in proliferation response to drugs and growth factors between MCF7 cells which do not have propensity to form me-
tastases in animal models and MDA-MB-231 cells which may form metastases upon inoculation into animals. Several of these
differences are unexpected and confirmed by clinical observations.
Key Words: breast cancer, combinatorial treatment, EGF, oestrogen, TGFβ.
Combinatorial treatments are a promising way
to improve treatment outcomes in cancer with
decreased resistance development and toxicity.
However, cross-talk mechanisms between the drugs
may produce unexpected toxicities [1]. Combined
effects of drugs are difficult to predict and may show
different synergistic or antagonistic effects depending
on the signalling status of the cells being targeted [2].
In addition, tumour cells are under constant
influence of physiological regulators which affect
the tumourigenic properties of the cells and are often
deregulated in cancer. There have been reported
a number of studies of various combinations of cell
regulators. For example, Sutherland et al. reported
a study of IGF-1, EGF, TGFβ and bFGF effects on the
proliferation of T-47D cells [3]. Additionally, the proli-
ferative response of human breast cancer cells to poly-
peptide growth factors has been found to be modified
by oestrogen signalling [4] and ER-EGF signalling
cross-talk has been implicated in development
of treatment resistance [5]. These and other similar
studies have shown that combinations of regulators
may have unexpected impacts on cell proliferation
and that these impacts are combination-specific and
not simply the sums of single treatments. An extensive
intracellular signalling cross-talk may explain combi-
natorial effects, and signalling differences between
patients may have an impact on differences in indi-
vidual patient response [6].
Considering cross-talk both between the different
drugs in a treatment combination and between cell
signalling pathways in the patient treated, it is neces-
sary to study the impact of drug combinations on cells
in different signalling states in order to optimise treat-
ment with combinatorial regimens.
EGF, TGFβ and oestrogen are among the most
potent regulators of human breast epithelial tumouri-
genesis, and deregulation of all these pathways is as-
sociated with different steps in tumour progression.
Oestrogen signalling drives proliferation in normal
breast epithelial cells, and deregulation leads first
to hyperplasia and thereafter to atypical hyperplasia,
the stage before carcinoma in situ. It also contri butes
to genetic instability, a hallmark of cancer [7]. EGFR
deregulation sustains proliferative signalling and
contributes to development of hormone-independent
growth in originally oestrogen-dependent cells.
It also induces angiogenesis and metastasis and
overexpression correlates with worse prognosis [8].
TGFβ1 is a factor inhibiting the growth of tumours
at an early stage in breast cancer, but deregulation
in later stages makes TGFβ contribute to development
of metastasis [9]. Cross-talk mechanisms between
these pathways have been studied [10–12], but there
are no screening studies including both drugs and
growth factors acting on the pathways. Our aim was
Submitted: April 14, 2014.
*Correspondence: E-mail: serhiy.souchelnytskyi@ki.se
Abbreviations used: bFGF — basic fibroblast growth factor; EGF —
epidermal growth factor; EGFR — epidermal growth factor recep-
tor; ER — oestrogen receptor; HER2 — human epidermal growth
factor receptor 2; IGF-1 — insulin-like growth factor 1; PR — pro-
gesterone receptor; TGFα — transforming growth factor-alpha;
TGFβ — transforming growth factor-beta.
Exp Oncol 2014
36, 2, 67–71
ORIGINAL CONTRIBUTIONS
68 Experimental Oncology 36, 67–71, 2014 (June)
thus to perform a combinatorial proliferation screening
of both drugs and ligands acting on these pathways
in order to find treatment combinations attractive for
further study, which may aid in personalising cancer
treatment.
We report a systematic analysis of combinato-
rial treatments with TGFβ1, EGF, 17β-oestradiol,
Tamoxifen, EGFR kinase inhibitor Iressa and TGFβ
type I receptor kinase inhibitor SB431542 of MCF7 and
MDA-MB-231 cells, studying the impact on cell prolif-
eration of 90 different combinations of drug and growth
factor. There was reported that these cells have dif-
ferent levels of tumourigenic transformation. Notably,
in the most of studies, MCF7 cells do not have propen-
sity to form metastases in animal models, while MDA-
MB-231 cells may form metastases upon inoculation
into animals. Despite that there were observations
that both these cell lines may or may not form tumours
and metastases, MCF7 cells are considered as cells
at first steps of transformation, and MDA-MB-231 cells
are considered as a model of advance transformed
cells [13–15]. For validation of the scre ening findings,
we performed meta-analysis of clinical data. This ap-
proach revealed several unexpected combinatorial
effects which were found experimentally and validated
through the meta-analysis, notably that the effects
of TGFβ are dependent on cross-talk with EGF and
oestrogen signalling. In conclusion, this study has
pointed to a number of interesting synergistic and
antagonistic interactions which may be further studied
to aid in personalisation of cancer treatment.
MATERIALS AND METHODS
Cells and reagents. MDA-MB-231 and MCF7 cells
were obtained from ATCC (Mannasas, VA) and cultured
as recommended. MDA-MB-231 cells form metasta-
ses when injected in animals, while MCF7 may form tu-
mours but do not form metastases. Cells were cultured
in DMEM medium (Gibco, Carlsbad, CA) with 10%
FBS and 1% antibiotics (penicillin and streptomycin).
The cells were monitored for absence of contamina-
tions, e.g. mycoplasma, and for transformation status
by measuring cells’ colony formation, clonogenicity,
contact inhibition, proliferation rates and morphology.
Human recombinant EGF and human recombinant
TGFβ1 were obtained from Peprotech (Rocky Hill,
USA), and 17β-oestradiol was obtained from Sigma-Al-
drich (Stockholm, Sweden). Tamoxifen, SB431542 and
Iressa were obtained from Sigma-Aldrich.
Treatments. In total, 90 combinations were used
for each cell line. 18 combinations of growth factors
were used, with TGFβ1 at concentrations of 1 and
10 ng/ml, EGF at 50 and 100 ng/ml and 17β-oestradiol
at 10 μM. The growth factors treatments (18 combina-
tions) were combined with the following 5 combina-
tions of drug treatments: none, 10 μM SB431542,
1 μM Tamoxifen, 10 μM Iressa and SB431542, Tamoxi-
fen and Iressa together at the above concentrations.
MTT assay. Cell proliferation was measured by MTT
assay (Promega, Madison, WI). The MTT assays were
performed as described in earlier studies [16]. Cells
were seeded in 96-well plates at 10 000 cells/well
in culturing medium. The next day, fresh medium and
treatments were added. Four wells were used as re-
peats for each condition. Cells were incubated for 48 h,
whereafter MTT assay was performed and proliferation
measured as absorbance at 570 nm in a spectropho-
tometer. Representative experiments of three repeats
are shown in figures. Significance of differences was
calculated by Student’s t-test.
Clinical correlations. Meta-analysis of clinical
data has previously been used to study drug interac-
tions [17]. For relevant clinical correlations, we searched
for microarray studies containing clinical outcome data
and analysis of TGFβ1 and EGF ligand expression, since
these ligands were included in our screening.
The study by Lyng et al. [18] comprised 108 ER-
positive patients with invasive ductal or lobular carci-
nomas treated with Tamoxifen. Enhanced TGFβ1 and
EGF expression were defined by two of three probes for
each protein having expression values above the total
patient average.
The study by Ellsworth et al. [19] included twenty
breast cancer patients with lymph node metastases
>2.0 mm of different histology and ER/PR/HER2 status
and studied the difference in gene expression between
primary tumours and paired metastatic lymph nodes.
We calculated expression quotas between lymph
nodes and primary tumour for each patient. Enhanced
TGFβ1 expression was defined where the quota for
one of two probes was above the average quota, and
enhanced EGF expression was defined by the single
EGF probe quota being above the average quota. Sig-
nificant differences were calculated by Student’s t-test
in analysis of both studies.
RESULTS
Proliferation screening. We tested the effects
of combinations of Iressa, SB431542, Tamoxifen,
TGFβ1, EGF and 17β-oestradiol on cell prolifera-
tion (Fig. 1). The 90 tested conditions are indicated
in the Material and Methods section. Here we describe
those conditions which showed unexpected and novel
responses of cells to treatments.
EGF
TGFβ
17β-Oestradiol
Iressa
SB431542
Tamoxifen
cell
proliferationIn
hi
bi
tio
n
St
im
ul
at
io
n
Fig. 1. Schematic presentation of the treatments. Links of EGF
and 17β-oestradiol to growth-promoting, and TGFβ to growth-
inhibitory effects are presented. Effects of Iressa, SB431542 and
Tamoxifen on EGF, TGFβ and 17β-oestradiol regulated signalling
are indicated
Experimental Oncology 36, 67–71, 2014 (June) 69
The effect of TGFβ1 is dependent on cross-talk with
the other treatments. MCF7 cells generally showed
a trend towards inhibition by TGFβ1, while in MDA-
MB-231 cells, an inhibitory effect of TGFβ1 was only
seen in cells co-treated with EGF and 17β-oestradiol
(Fig. 2). This shows that an inhibitory effect may
be enhanced by treatment with two traditional growth
stimulators. Further support for the importance
of oestrogen and TGFβ signalling cross-talk is pro-
vided by the fact that MDA-MB-231 cells treated with
ER antagonist Tamoxifen were inhibited in a TGFβ1-
concentration-dependent manner, while MCF7 cells
on the other hand were inhibited upon addition of EGF
or oestrogen regardless of TGFβ1 concentration
(Fig. 3). Since MDA-MB-231 cells are ER-, this, as well
as the stimulatory effect seen by Tamoxifen alone, may
point to Tamoxifen off-ER-target effects.
MDA-MB-231 without drugs
**
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Control EGF 100 ng/ml 17β-Oestradiol
10 μM
EGF +
17β-Oestradiol
Pr
ol
ife
ra
tio
n
(5
70
n
m
a
bs
or
ba
nc
e)
No TGFβ
TGFβ 1 ng/ml
MCF7 without drugs
0
0.5
1
1.5
2
2.5
Control EGF 100 ng/ml 17β-Oestradiol
10 μM
EGF +
17β-Oestradiol
Pr
ol
ife
ra
tio
n
(5
70
n
m
a
bs
or
ba
nc
e)
a
b
Fig. 2. Proliferation of MDA-MB-231 and MCF7 without ad-
dition of drugs shows the combination of EGF, 17β-oestradiol
and TGFβ1 to inhibit proliferation in MDA-MB-231 but not
in MCF7 cells. Treatment conditions are annotated. **(p < 0.01)
is in comparison with untreated cells
While Iressa did inhibit MDA-MB-231 cells, TGFβ1 did
not have an additional inhibitory effect, but rather blocked
the stimulatory effect of EGF, showing that the effect
of TGFβ also depends on EGF signalling (Fig. 4).
Treatment of cells with all three inhibitors — Iressa,
Tamoxifen and SB431542 — showed the same trends
in effects on proliferation as untreated cells (see
Fig. 2), with the difference that EGF + 17β-oestradiol
treatment inhibited MDA-MB-231 cells regardless
of TGFβ treatment (Fig. 5), providing further evidence
that the effect of drugs in combination is not simply
an addition of the single drug effects, but the result
of signalling cross-talk.
Meta-analysis of clinical correlations. Through
meta-analysis of original data reported by Ells-
worth et al. [19], which focused on gene signatures
predicting metastasis, we found that an increased
rate of TGFβ1 and EGF ligand co-expression in lymph
node metastases compared with primary tumours from
the same patients significantly correlated with a lower
number of positive lymph nodes (Fig. 6, a), implying
that in the metastatic process, cells co-expressing
TGFβ and EGF are less prone to metastasize. While
the original data did not allow the evaluation of an ad-
ditional impact of oestrogen signalling, the available
meta-data confirm our observations of the inhibitory
effects on cell proliferation by TGFβ1 being dependent
on EGF (see Fig. 2).
MDA-MB-231 Tamoxifen
**
**
* **
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Pr
ol
ife
ra
tio
n
(5
70
n
m
a
bs
or
ba
nc
e)
Untreated control
No TGFβ
TGFβ 1 ng/ml
TGFβ 10 ng/ml
MCF7 Tamoxifen
* ** * * *
0
0.5
1
1.5
2
2.5
3
Pr
ol
ife
ra
tio
n
(5
70
n
m
a
bs
or
ba
nc
e)
a
b
Control EGF 100 ng/ml 17β-Oestradiol
10 μM
EGF +
17β-Oestradiol
Control EGF 100 ng/ml 17β-Oestradiol
10 μM
EGF +
17β-Oestradiol
Fig. 3. Proliferation of MDA-MB-231 and MCF7 cells treated
with 1 μM Tamoxifen shows MDA-MB-231 proliferation to de-
crease in a TGFβ1-dependent manner. MCF7 cells are inhibited
by 17β-oestradiol and EGF independent of TGFβ1. Treatment
conditions are annotated. For MCF7, significant differences are
in comparison to Tamoxifen only (*p < 0.05; **p < 0.01)
Meta-analysis of the study by Lyng et al. [18], com-
prising 108 ER+ patients treated with Tamoxifen, found
that patients with above average TGFβ1 expression had
smaller tumours than both patients where TGFβ1 and
EGF were co-expressed and the total patient average
(Fig. 6, b), while patients with above average EGF expres-
sion had a lower grade of malignancy (Fig. 6, c). Other
variations in clinical observations and TGFβ and EGF
activities were found to be not significant. These data
support our observations where the proliferation in both
cell lines was decreased when Tamoxifen was combined
with TGFβ1 (MDA-MB-231) or EGF (MCF7) (see Fig. 3).
70 Experimental Oncology 36, 67–71, 2014 (June)
MDA-MB-231 Iressa
** **
*
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
Pr
ol
ife
ra
tio
n
(5
70
n
m
a
bs
or
ba
nc
e) Untreated control
No TGFβ
TGFβ 1 ng/ml
MCF7 Iressa
0
0.5
1
1.5
2
2.5
3
Pr
ol
ife
ra
tio
n
(5
70
n
m
a
bs
or
ba
nc
e)
a
b
Control EGF 100 ng/ml 17β-Oestradiol
10 μM
EGF +
17β-Oestradiol
Control EGF 100 ng/ml 17β-Oestradiol
10 μM
EGF +
17β-Oestradiol
Fig. 4. Proliferation of MDA-MB-231 and MCF7 cells upon treat-
ment with 10 μM Iressa shows EGF to have a stimulatory effect,
which is counteracted by addition of TGFβ1, in the presence
of Iressa in MDA-MB-231 cells. “Untreated control” indicates
condition with no treatments. Treatment conditions are annotated
(*p < 0.05, **p < 0.01)
MDA-MB-231 Iressa, Tamoxifen, SB431542
**
* *
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
Pr
ol
ife
ra
tio
n
(5
70
n
m
a
bs
or
ba
nc
e) Untreated control
No TGFβ
TGFβ 1 ng/ml
MCF7 Iressa, Tamoxifen, SB431542
0
0.5
1
1.5
2
2.5
Pr
ol
ife
ra
tio
n
(5
70
n
m
a
bs
or
ba
nc
e)
a
b
Control EGF 100 ng/ml 17β-Oestradiol
10 μM
EGF +
17β-Oestradiol
Control EGF 100 ng/ml 17β-Oestradiol
10 μM
EGF +
17β-Oestradiol
Fig. 5. Proliferation of MDA-MB-231 and MCF7 cells exposed
to 10 μM Iressa, 1 μM Tamoxifen and 10 μM SB431542 shows
combined application of EGF and 17β-oestradiol to inhibit MDA-
MB-231 cells. Treatment conditions are annotated. “Untreated
control” indicates condition with no treatments. Significant
differences *(p < 0.05) and **(p < 0.01) are in comparison with
cells treated only with the three inhibitors
15
10
5
EGF
* *
**
Nu
m
be
r o
f p
os
iti
ve
ly
m
ph
n
od
es
AllTGFβ EGF + TGFβ
80
60
20
40
EGF
*
*
**
**
Tu
m
ou
r s
ize
, m
m
Tu
m
ou
r g
ra
de
AllTGFβ EGF + TGFβ
3
2.5
1
1.5
2
EGF AllTGFβ EGF + TGFβ
a
b
c
Fig. 6. Clinical outcomes of TGFβ and EGF co-expression.
a) Meta-analysis of data reported by the study by Ells-
worth et al. [19] shows TGFβ1 and EGF co-expression in lymph
node metastases to correlate with fewer positive lymph nodes.
b) Meta-analysis of data reported by the study by Lyng et al. [18]
on Tamoxifen-treated patients shows TGFβ1 expression to cor-
relate with smaller tumours. Significant differences *(p < 0.05)
and **(p < 0.01) are in comparison with the group showing
enhanced TGFβ expression. c) In the study by Lyng et al. [18],
EGF expression was associated with a lower grade of malignancy.
**(p < 0.01) and *(p < 0.05) are in comparison with EGF condition
DISCUSSION
It is an accepted fact that combinations of multiple
cellular regulators may have different impacts as com-
pared to the sum of the same regulators applied indi-
vidually. Thus, it is necessary to study multiple interac-
tions not only between potential drug candidates but
also the interplay between the drugs and the different
growth factors whose signalling is deregulated in can-
cer cells. Our study focused on exploring the effects
on cell proliferation by TGFβ1, EGF, 17β-oestradiol,
Tamoxifen, Iressa and SB431542. We observed diffe-
rences in response between the ER− MDA-MB-231 and
ER+ MCF7 cell lines.
Experimental Oncology 36, 67–71, 2014 (June) 71
The main novel findings were 1) that TGFβ1 inhibi-
ted proliferation of MDA-MB-231 cells when the cells
are also treated with EGF and oestrogen, 2) that
exposure of MDA-MB-231 cells to Tamoxifen, EGF
and/or 17β-oestradiol promoted the inhibitory effect
of TGFβ1, while combinations of Tamoxifen, EGF and/
or 17β-oestradiol inhibited MCF7 proliferation irre-
spectively of TGFβ1 addition, 3) that addition of EGF
to Iressa had a stimulatory effect, which was blocked
by TGFβ1, in MDA-MB-231 cells, and 4) that co-treat-
ment with Iressa, Tamoxifen and SB431542 showed
the same general response trend as untreated cells.
The latter fact implies a cross-inhibition between
the drugs, further underlining the fact that addition
of new drugs, proven effective when used alone,
to existing treatment regimens, may have a negative
effect. Tamoxifen alone somewhat increased MDA-
MB-231 cell proli feration. Since these cells are ER−,
this is not completely unexpected. Tamoxifen has
earlier been observed to increase the proliferation
of Tamoxifen-resistant breast cancer cells [20].
The correlations between TGFβ and EGF gene ex-
pression and clinical outcomes confirm certain of our
findings, showing impact on tumour size and grade
when EGF or TGFβ are combined with Tamoxifen, and
a reduction in lymph node metastasis upon TGFβ-EGF
co-expression.
Our findings underline the need for in-depth study
of drug and growth factor interactions before applica-
tion of any combinatorial regimen in cancer treatment.
This study particularly highlights the different roles
of TGFβ in regulating cell proliferation, and how the im-
pact of TGFβ is dependent on cell type and cross-talk
with EGF and oestrogen signalling.
ACKNOWLEDGMENTS
We are grateful to the Oves Minnesfond for support
and encouragement. This work is supported in part
by grants from the Radiumhemmet research funds
(№ 121202), the Swedish Cancer Society, the Swe-
dish Research Council, the Swedish Institute, INTAS,
Erasmus KI-UWM and STINT to S.S., and by MD/PhD
program to M.M.
CONFLICT OF INTERESTS
The authors declare no conflict of interests.
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Copyright © Experimental Oncology, 2014
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| id | nasplib_isofts_kiev_ua-123456789-145334 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1812-9269 |
| language | English |
| last_indexed | 2025-12-01T14:51:34Z |
| publishDate | 2014 |
| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Mints, M. Souchelnytskyi, S. 2019-01-20T16:22:05Z 2019-01-20T16:22:05Z 2014 Impact of combinations of EGF, TGFβ, 17β-oestradiol, and inhibitors of corresponding pathways on proliferation of breast cancer cell lines / M. Mints, S. Souchelnytskyi // Experimental Oncology. — 2014. — Т. 36, № 2. — С. 67-71. — Бібліогр.: 20 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/145334 Aim: The impact of combinations of anti-cancer drugs and growth factors on tumour cells may differ from the assumed sum of the effects of each factor separately. Therefore it is important to study the effects of different combinations of various drugs and treatments. Our aim was to study the effects on breast cancer cell proliferation of EGF, TGFβ and 17β-oestradiol, three important regulators of breast tumourigenesis, and their respective inhibitors in different combinations. Materials and Methods: We screened the effects on proliferation of MCF7 and MDA-MB-231 cells of ninety different combinations of EGF, TGFβ and 17β-oestradiol, Iressa, SB431542 and Tamoxifen. Meta-data analysis of available clinical data was performed to validate observed proliferation data. Results: In MDA-MB-231 cells, TGFβ1 was found inhibitory when cells were simultaneously treated with EGF and 17β-oestradiol, with the effect potentiated by addition of all inhibitors combined. In the same cells, Iressa when combined with EGF was paradoxically stimulatory. Tamoxifen inhibited MCF7 cells co-treated with EGF or oestrogen, and enhanced the inhibitory effect of TGFβ in MDA-MB-231 cells. Meta-analysis of clinical gene expression studies confirmed several of these points, showing enhanced TGFβ and EGF expression in Tamoxifen-treated patients to correlate with decreased tumour size and grade respectively, and combined TGFβ-EGF expression to decrease the risk of metastasis. Conclusion: Our study shows significant differences in proliferation response to drugs and growth factors between MCF7 cells which do not have propensity to form metastases in animal models and MDA-MB-231 cells which may form metastases upon inoculation into animals. Several of these differences are unexpected and confirmed by clinical observations. Key Words: breast cancer, combinatorial treatment, EGF, oestrogen, TGFβ. We are grateful to the Oves Minnesfond for support and encouragement. This work is supported in part by grants from the Radiumhemmet research funds (№ 121202), the Swedish Cancer Society, the Swedish Research Council, the Swedish Institute, INTAS, Erasmus KI-UWM and STINT to S.S., and by MD/PhD program to M.M. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Original contributions Impact of combinations of EGF, TGFβ, 17β-oestradiol, and inhibitors of corresponding pathways on proliferation of breast cancer cell lines Article published earlier |
| spellingShingle | Impact of combinations of EGF, TGFβ, 17β-oestradiol, and inhibitors of corresponding pathways on proliferation of breast cancer cell lines Mints, M. Souchelnytskyi, S. Original contributions |
| title | Impact of combinations of EGF, TGFβ, 17β-oestradiol, and inhibitors of corresponding pathways on proliferation of breast cancer cell lines |
| title_full | Impact of combinations of EGF, TGFβ, 17β-oestradiol, and inhibitors of corresponding pathways on proliferation of breast cancer cell lines |
| title_fullStr | Impact of combinations of EGF, TGFβ, 17β-oestradiol, and inhibitors of corresponding pathways on proliferation of breast cancer cell lines |
| title_full_unstemmed | Impact of combinations of EGF, TGFβ, 17β-oestradiol, and inhibitors of corresponding pathways on proliferation of breast cancer cell lines |
| title_short | Impact of combinations of EGF, TGFβ, 17β-oestradiol, and inhibitors of corresponding pathways on proliferation of breast cancer cell lines |
| title_sort | impact of combinations of egf, tgfβ, 17β-oestradiol, and inhibitors of corresponding pathways on proliferation of breast cancer cell lines |
| topic | Original contributions |
| topic_facet | Original contributions |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/145334 |
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