Kinase suppressor of Ras 2 is involved in regulation of cell proliferation and is up-regulated in human invasive ductal carcinomas of breast
Aim: To study the expression of Kinase Suppressor of Ras 2 (KSR2) in human breast tumors and its effect on proliferation of breast epithelial cells. We reported previously that KSR2 was up-regulated in immortalized human breast epithelial cells. Methods: Proteomics technologies, systems biology tool...
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| Опубліковано в: : | Experimental Oncology |
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| Дата: | 2010 |
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| Формат: | Стаття |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2010
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| Цитувати: | Kinase suppressor of Ras 2 is involved in regulation of cell proliferation and is up-regulated in human invasive ductal carcinomas of breast / M. Jia, S. Souchelnytskyi // Experimental Oncology. — 2010. — Т. 32, № 3. — С. 209-212. — Бібліогр.: 12 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1859617160801812480 |
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| author | Jia, M. Souchelnytskyi, S. |
| author_facet | Jia, M. Souchelnytskyi, S. |
| citation_txt | Kinase suppressor of Ras 2 is involved in regulation of cell proliferation and is up-regulated in human invasive ductal carcinomas of breast / M. Jia, S. Souchelnytskyi // Experimental Oncology. — 2010. — Т. 32, № 3. — С. 209-212. — Бібліогр.: 12 назв. — англ. |
| collection | DSpace DC |
| container_title | Experimental Oncology |
| description | Aim: To study the expression of Kinase Suppressor of Ras 2 (KSR2) in human breast tumors and its effect on proliferation of breast epithelial cells. We reported previously that KSR2 was up-regulated in immortalized human breast epithelial cells. Methods: Proteomics technologies, systems biology tool for a KSR2 network analysis, immunoblotting, siRNA technology, overexpression of KSR2, cell proliferation assays and immunohistochemistry of tissue microarray of human breast tumors and normal breast tissue were used. Results: In conditionally immortalized primary epithelial cells KSR2 expression was shown to be up-regulated. The involvement of KSR2 in regulation of cell proliferation was predicted by a KSR2-centered network analysis. We observed that KSR2 down-regulation with specific siRNA inhibited cell proliferation. By immunohistochemistry of tissue microarray it was demon strated that KSR2 expression was enhanced in human invasive breast carcinomas. Conclusion: Our findings propose KSR2 as a new marker of immortalization, which has an impact on cell proliferation.
|
| first_indexed | 2025-11-28T20:07:46Z |
| format | Article |
| fulltext |
Experimental Oncology 32, 209–212, 2010 (September) 209
Acquisition of immortalization by somatic cells is
one of the hallmarks of tumorigenesis [1, 2]. Immor-
talization is a complex process, which involves not only
activation of telomerase (TERT), but also changes in
a number of signalling mechanisms related to regula-
tion of cell proliferation and apoptosis [3–5]. Among
such cell cycle regulators are cyclin-dependent kinase
inhibitor p16INK4a, p53, MAP kinase and pRb (reviewed
in [3–5]). Further studies are expected to unveil the
whole complexity of immortalization, and to describe
all involved proteins and genes.
Kinase Suppressor of Ras 2 (KSR2) is a scaffold pro-
tein involved in activation of MAP kinase pathway [6, 7].
KSR2 was found to mediate A-Raf signalling. However,
a screening for KSR2 interacting proteins showed that
KSR2 may play a broader role in regulation of cell pro-
liferation, by forming high-order complex(es) including
kinases (MEK1, MEK2, Erk2, p38, cdk4, PI3K) and
phosphatases (PP2A, PP6), translational, ribosomal,
transport and structural proteins [8]. These findings
indicated that KSR2 may play a role in tumorigenesis.
A model of immortalization of human breast epi-
thelial cells was recently developed using conditional
immortalization of primary cells [9]. Temperature-
sensitive construct of SV40 LT in combination with
hTERT allowed controlled immortalization of human
primary cells [9]. This model of immortalization was
found suitable for studies of signalling mechanisms
of the transition from immortalization to senescence.
Proteome profiling of these cells showed that im-
mortalization-to-senescence transition leads to the
changes in expression of a number of proteins [10].
Some of them, like KSR2, could be directly involved
in regulation of cell proliferation.
MATERIAL AND METHODS
Cells. 184A1 and MCF10A cells were obtained from
ATCC (Manassas, USA), and were cultured in media
recommended by ATCC. Conditionally immortalized
human primary epithelial cells were generated using
constructs and methods described early by O´Hare et
al. [9]. Notably, the catalytic subunit of human telom-
erase (hTERT) and a temperature-sensitive mutant
of simian virus 40 large-tumor antigen were used
(non-DNA binding non-Bub1 binding thermolabile T
antigen; [9]). The luminal 226Lts4 and 226LU19 cells
were used. Expression of LT antigen was confirmed by
immunoblotting, and hTERT was monitored by TRAP
assay (O’Hare and Jat; manuscript).
Proteomics. Proteome profiling of conditionally
immortalized cells, two-dimensional gel electropho-
resis, gel image analysis and MALDI TOF mass spec-
trometry for identification of differentially expressed
proteins were described by Jia et al. [10].
Network analysis of KSR2 for interactors.
FunCoup tool was used to identify KSR2 interactors
(http://funcoup.sbc.su.se). FunCoup operates with
databases which have been selected for their thorough
analysis and incorporation of experimental data. This
ensures that only confirmed by multiple laboratories
results are taken into consideration for building a net-
work. Settings for the network analysis were as follows:
confidence score 0.10, only direct one-step interactors
observed in humans were considered.
Transfections and immunoblotting. Cells were
transfected in 6-wells plates by LipofectAMINE 2000 re-
agent, as recommended by the supplier (Invitrogen,
Carlsbad, USA). pcDNA3-KSR2 construct was kindly
provided by Dr. Jiahuai Han. siRNA to KSR2 (ID # 41069)
KINASE SUPPRESSOR OF RAS 2 IS INVOLVED IN REGULATION
OF CELL PROLIFERATION AND IS UP-REGULATED IN HUMAN
INVASIVE DUCTAL CARCINOMAS OF BREAST
M. Jia, S. Souchelnytskyi*
Department of Oncology-Pathology, Karolinska Biomics Center, Z5:01, Karolinska University Hospital,
Solna, SE-17176, Karolinska Institutet, Stockholm, Sweden
Aim: To study the expression of Kinase Suppressor of Ras 2 (KSR2) in human breast tumors and its effect on proliferation of
breast epithelial cells. We reported previously that KSR2 was up-regulated in immortalized human breast epithelial cells. Methods:
Proteomics technologies, systems biology tool for a KSR2 network analysis, immunoblotting, siRNA technology, overexpression
of KSR2, cell proliferation assays and immunohistochemistry of tissue microarray of human breast tumors and normal breast
tissue were used. Results: In conditionally immortalized primary epithelial cells KSR2 expression was shown to be up-regulated.
The involvement of KSR2 in regulation of cell proliferation was predicted by a KSR2-centered network analysis. We observed
that KSR2 down-regulation with specific siRNA inhibited cell proliferation. By immunohistochemistry of tissue microarray it was
demon strated that KSR2 expression was enhanced in human invasive breast carcinomas. Conclusion: Our findings propose KSR2 as
a new marker of immortalization, which has an impact on cell proliferation.
Key Words: KSR2, proliferation, human breast epithelial cells, breast cancer, invasive ductal carcinoma.
Received: June 21, 2010.
*Correspondence: Fax: +46 (0) 8–517–71 000
E-mail: serhiy.souchelnytskyi@ki.se
Abbreviations used: hTERT — catalytic subunit of human telomer-
ase; IDC — invasive ductal carcinoma; KSR2 — kinase suppressor
of Ras 2; LT — simian virus 40 large-tumor antigen; MAPK — mi-
togen activated protein kinase.
Exp Oncol 2010
32, 3, 209–212
210 Experimental Oncology 32, 209–212, 2010 (September)
was obtained from Ambion (Austin, USA). Control scram-
bled siRNA (sc-37007) were obtained from SantaCruz
Biotech (Santa Cruz, USA). Media was changed 6 hs
after transfection. For immunoblotting, cell lysates were
resolved on SDS polyacrylamide gels and transferred
onto Hybond P membranes (GE Healthcare, Piscataway,
NJ). Membranes were blocked with 5% (v/v) BSA and
then incubated with a primary antibody against KSR2
(H00283455-A01; Abnova, Taiwan) as recommended by
manufacturer, and followed by an HRP-conjugated sec-
ondary antibody (GE Healthcare, Uppsala, Sweden). The
proteins were visualized using Western Blotting Luminol
Reagents (Santa Cruz Biotechnology Inc.). For transfec-
tion with siRNA, cells were seeded in 24-well plates, and
transfection procedure was performed the next day, as
recommended by the siRNA suppliers. After transfection,
cells were cultured in a medium supplemented with 10%
FBS before assays.
Cell proliferation assays. Cell proliferation was
measured using [3H]thymidine incorporation assay and
CellTiter 96® Non-Radioactive Cell Proliferation Assay
(MTT assay) (Promega, Promega Biotech AB, Stock-
holm, Sweden). 184A1 and MCF10A cells were seeded
in plates for proliferation assays. Cells were incubated
with 0.1 Ci/ml of [3H]thymidine for the last 24 hs of the
72 hs incubation time period. Radioactivity incorporated
in DNA was measured as described earlier [11]. MTT
assay was performed in parallel with [3H]thymidine-
incorporation test, except that no radioactivity was
added. Cells were grown for the 72 hours, and MTT
assay was performed according to the manufacturer’s
recommendations. Statistical significance of observed
differences was evaluated using Student’s t-test.
Immunohistochemistry. AccuMax breast cancer
arrays (ISU ABXIS Co., Ltd, Seoul, South Korea) were
used. Each array slide contains 45 cases of cancer
tissues and 4 non-neoplastic tissues. Arrays were
stained with anti-KSR2 antibody (H00283455-A01;
Abnova) at a dilution of 1:250. Antigen retrieval was
performed using DakoCytomation target retrieval solu-
tion high pH (DAKO, Carpinteria, CA, USA). The slides
were stained with VECTASTAIN Elite ABC kits (Vector
Laboratories Inc., Burlingame, CA, USA) following
the manufacturer’s instruction, counterstained with
hematoxylin and mounted with Fluoromount G (Sou-
thern Biotechnology, Birmingham, AL). The stained
tissues were photographed using a Leica DFC camera
and images were acquired with Leica QWin Standard
software (Leica Microsystems Imaging Solutions Ltd,
Cambridge, UK). Intensity of staining was evaluated as
absent ((-), no staining or weak staining in fewer than
5% of cells) middle/present ((+), staining in > 5% but
< 50% of cells), and strong ((++), staining in > 50%
of cells). Staining was evaluated in tumor cells and
epithelial cells of normal tissues.
RESULTS AND DISCUSSION
Using proteomics approach KSR2 was identified
as an up-regulated protein in immortal human primary
epithelial cells [10]. Protein spot containing KSR2 was
detected only in immortal cells, which indicated
up-regulation of at least more than 2 fold (Fig. 1).
Conditionally immortalized cells were generated by
expression of hTERT and temperature-sensitive mu-
tant (U19tsA58) of simian virus 40 large-tumor (LT)
antigen, as described by O´Hare et al. [9].
Non-immortal Immortal
KSR2
Fig. 1. Images of inserts of 2D gels which show the protein
spots of KSR2. Images show the KSR2 spot in 2D gels from
cells cultured under permissive (Immortal) and non-permissive
(Non-immortal) conditions. Arrows indicate migration position
of the protein spot of KSR2.
KSR2 is a scaffold protein in mitogen-activated
protein kinase (MAPK) pathways [6–8]. To explore
potential impact of KSR2 on cell proliferation and
generic MAPK pathways in unbiased way, we used
FunCoup tool (http://funcoup.sbc.su.se). The gene-
rated network (Fig. 2) showed potential involvement of
Raf-1, mitogen-activated kinases 1 and 3 (MAPK1 and
MAPK3), mitogen-activated kinase kinase 1 (MAP2K1)
and MAPK scaffold protein 1 (MAPKSP1) (Fig. 2).
These molecules provide further links to regulators of
the cell cycle, p53 and hTERT (data not shown). A num-
ber of other KSR2 interactors involved in regulation
of the cell cycle were reported, although they have to
be validated [8]. Thus, analysis of the KSR2-centered
network indicated that KSR2 may have an impact on
cell proliferation.
KSR2
MAPKSP1 MAPK3
MAPK1
RAF1
MAP2K1
Fig. 2. KSR2 forms a network with components of Raf/MAP ki-
nase signalling. The network of interacting proteins was built with
KSR2 as a hub, using FunCoup tool (http://funcoup.sbc.su.se).
To manipulate KSR2 level in cells subjected to
cell proliferation assays, we enhanced expression of
KSR2 by transfecting cells with a specific vector or
down-regulated KSR2 with a specific siRNA (Fig. 3).
We studied two human breast epithelial cell lines,
MCF10A and 184A1, which are both non-tumorigenic
and considered to have normal phenotype of human
breast epithelial cells. These cells can be cultured
in vitro, and therefore are immortalized. Both cell lines
also express KSR2 (Fig. 3). However, 184A1 cells may
undergo immortalization crisis, and have lower prolif-
eration potential, as compared to MCF10A cells [12].
Experimental Oncology 32, 209–212, 2010 (September) 211
Control
siRNA
siRNAMCF10A
p<0.025
184A1
p<0.005
KSR2
siRNA
Control
siRNA
KSR2
siRNA
KSR2 47.5 kDa
Ce
ll
pr
ol
ife
ra
tio
n
(3
H-
Td
in
co
rp
or
at
io
n;
c
m
p)
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
Empty
vector
Overexpression
MCF10A 184A1
p<0.25
KSR2
vector
Empty
vector
KSR2
vector
KSR2 47.5 kDa
Ce
ll
pr
ol
ife
ra
tio
n
(M
TT
; a
rb
itr
ar
y
un
its
)
1.4
1.2
1
0.8
0.6
0.4
0.2
0
a
b
Fig. 3. Down-regulation of KSR2 resulted in inhibition of the cell
proliferation. (a) 184A1 and MCF10A cells were transfected with
siRNA to KSR2, and with control siRNAs, as indicated. Prolifera-
tion of cells was monitored by measurement of [3H]thymidine
incorporation. (b) 184A1 and MCF10A cells were transfected with
KSR2 expressing vector, and with control empty pcDNA3 vec-
tor, as indicated. Cell proliferation was measured by MTT assay.
Expression of KSR2 (a,b) was monitored by immunobloting of
the whole cell extracts. Migration position of a 47.5 kDa marker
is indicated on the side of gel panel. Statistical significance in
assays was calculated by Student’s t-test.
We observed that down-regulation of KSR2 had a
strong inhibitory effect on proliferation of both cell lines
(Fig. 3a). KSR2 overexpression had rather weak ef-
fect on cell proliferation, which was more pronounced
for 184A1 cells, but not significant for MCF10A cells
(Fig. 3b). This could be explained by the presence of
endogenous KSR2 in a quantity already sufficient for
its normal functions. On the other hand, decrease in
KSR2 expression by siRNA, had an inhibitory impact
on proliferation of both cell lines, indicating the rate-
limiting role of KSR2. Thus, KSR2 is involved in main-
taining the cell proliferation rate.
To explore whether KSR2 expression could be
altered in breast tumors, we performed immunohisto-
chemistry study of human breast tissue microarray. The
microarray consisted of 29 cases of infiltrating ductal
carcinomas (IDC), 8 papillary carcinomas, 4 cases of
infiltrating lobular carcinomas (ILC) and 4 normal breast
tissues. We observed an increase of KSR2 staining in
epithelial cells of IDC tumors, as compared with normal
breast tissue (Fig. 4a, b). We observed KSR2 staining
in all 29 cases of IDC, 4 cases of ILC and 8 cases of
papillary carcinomas (Fig. 4c). All samples of normal
breast tissue did not show KSR2 staining. KSR2 stain-
ing in tumor samples was detected mainly in cytoplasm
of cells. No correlations of KSR2 expression with TNM
gradation of tumors were observed.
a
b
×200
×400
×200
×400
Samples Staining
(-) (+) (++)
Invasive Ductal Carcinoma (29 cases) 0 10 19
Invasive Lobular Carcinoma (4 cases) 0 2 2
Papillary Carcinoma (8 cases) 0 6 2
Normal (4 cases) 4 0 0
Fig. 4. Expression of KSR2 was increased in human infiltrating ductal
carcinomas. Representative images of immunohistochemistry stain-
ings for KSR2 are shown: (a) staining of normal human breast tissue;
(b) staining of an infiltrating ductal carcinoma case. Magnifications are
X200 (top images in panels) and X400 (lower images in panels). (c)
Quantification of KSR2 staining in human breast cancer. Evaluation
of staining was performed as described in the material and methods
section. Numbers indicate numbers of cases with corresponding
detection of staining (as (-), (+) and (++)), and the total number of
cases is mentioned in the left column.
212 Experimental Oncology 32, 209–212, 2010 (September)
KSR2 plays an important role in activation of vari-
ous signalling events, with reported role in signalling by
p38 MAPK and MAP2K3 [6–8]. We found that KSR2 is
involved in regulation of cell proliferation, and is up-
regulated in tumor epithelial cells in human invasive duc-
tal, invasive lobular and papillary carcinomas of breast.
In conclusion, our findings provide evidence of a potential
role of KSR2 in tumorigenesis, indicating that expression
of KSR2 may be changed already upon acquisition by
cells the ability to non-limited proliferation.
ACKNOWLEDGEMENTS
We are grateful to Carina Hellberg for advice on
immunohistochemistry. This work is supported in
part by grants from the programmes of the Dept. of
Oncology-Pathology, Karolinska Institutet, Ludwig
Institute for Cancer Research, the Swedish Cancer
Society, the Swedish Research Council, the Swedish
Institute, the EU program RTN «EpiPlastCarcinoma»,
INTAS, UICC/American Cancer Society, Hiroshima
University and Merck KGaA to S.S.
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breast epithelial cells identified MAP2K3 as a senescence-
promoting protein which is down-regulated in human breast
cancer. Prot Clin Appl 2010; (in press).
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teome profiling of TGFbeta signaling: phosphorylation of tran-
scription factor –II-I (TFII-I) enhances cooperation of TFII-I
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Copyright © Experimental Oncology, 2010
|
| id | nasplib_isofts_kiev_ua-123456789-138608 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1812-9269 |
| language | English |
| last_indexed | 2025-11-28T20:07:46Z |
| publishDate | 2010 |
| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Jia, M. Souchelnytskyi, S. 2018-06-19T10:30:30Z 2018-06-19T10:30:30Z 2010 Kinase suppressor of Ras 2 is involved in regulation of cell proliferation and is up-regulated in human invasive ductal carcinomas of breast / M. Jia, S. Souchelnytskyi // Experimental Oncology. — 2010. — Т. 32, № 3. — С. 209-212. — Бібліогр.: 12 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/138608 Aim: To study the expression of Kinase Suppressor of Ras 2 (KSR2) in human breast tumors and its effect on proliferation of breast epithelial cells. We reported previously that KSR2 was up-regulated in immortalized human breast epithelial cells. Methods: Proteomics technologies, systems biology tool for a KSR2 network analysis, immunoblotting, siRNA technology, overexpression of KSR2, cell proliferation assays and immunohistochemistry of tissue microarray of human breast tumors and normal breast tissue were used. Results: In conditionally immortalized primary epithelial cells KSR2 expression was shown to be up-regulated. The involvement of KSR2 in regulation of cell proliferation was predicted by a KSR2-centered network analysis. We observed that KSR2 down-regulation with specific siRNA inhibited cell proliferation. By immunohistochemistry of tissue microarray it was demon strated that KSR2 expression was enhanced in human invasive breast carcinomas. Conclusion: Our findings propose KSR2 as a new marker of immortalization, which has an impact on cell proliferation. We are grateful to Carina Hellberg for advice on immunohistochemistry. This work is supported in part by grants from the programmes of the Dept. of Oncology-Pathology, Karolinska Institutet, Ludwig Institute for Cancer Research, the Swedish Cancer Society, the Swedish Research Council, the Swedish Institute, the EU program RTN «EpiPlastCarcinoma», INTAS, UICC/American Cancer Society, Hiroshima University and Merck KGaA to S.S. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Original contributions Kinase suppressor of Ras 2 is involved in regulation of cell proliferation and is up-regulated in human invasive ductal carcinomas of breast Article published earlier |
| spellingShingle | Kinase suppressor of Ras 2 is involved in regulation of cell proliferation and is up-regulated in human invasive ductal carcinomas of breast Jia, M. Souchelnytskyi, S. Original contributions |
| title | Kinase suppressor of Ras 2 is involved in regulation of cell proliferation and is up-regulated in human invasive ductal carcinomas of breast |
| title_full | Kinase suppressor of Ras 2 is involved in regulation of cell proliferation and is up-regulated in human invasive ductal carcinomas of breast |
| title_fullStr | Kinase suppressor of Ras 2 is involved in regulation of cell proliferation and is up-regulated in human invasive ductal carcinomas of breast |
| title_full_unstemmed | Kinase suppressor of Ras 2 is involved in regulation of cell proliferation and is up-regulated in human invasive ductal carcinomas of breast |
| title_short | Kinase suppressor of Ras 2 is involved in regulation of cell proliferation and is up-regulated in human invasive ductal carcinomas of breast |
| title_sort | kinase suppressor of ras 2 is involved in regulation of cell proliferation and is up-regulated in human invasive ductal carcinomas of breast |
| topic | Original contributions |
| topic_facet | Original contributions |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/138608 |
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