Correlation of iodine symporter expression in highly and low malignant cell lines of human breast cancer differed in their sensitivity to doxorubicin
Aim: To investigate the relationship of sodium/iodide symporter (NIS) expression with molecular phenotype of highly and low malignant cell lines of human breast cancer (BC) with different sensitivity to doxorubicin (Dox). Materials and Methods: The cell lines used in the analysis included T47D, MCF-...
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| Zitieren: | Correlation of iodine symporter expression in highly and low malignant cell lines of human breast cancer differed in their sensitivity to doxorubicin / N.Yu. Lukianova, A.V. Andriiv, V.F. Chekhun // Experimental Oncology. — 2016 — Т. 38, № 3. — С. 169-171. — Бібліогр.: 18 назв. — англ. |
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irk-123456789-1377412018-06-18T03:06:02Z Correlation of iodine symporter expression in highly and low malignant cell lines of human breast cancer differed in their sensitivity to doxorubicin Lukianova, N.Yu. Andriiv, A.V. Chekhun, V.F. Original contributions Aim: To investigate the relationship of sodium/iodide symporter (NIS) expression with molecular phenotype of highly and low malignant cell lines of human breast cancer (BC) with different sensitivity to doxorubicin (Dox). Materials and Methods: The cell lines used in the analysis included T47D, MCF-7, MDA-MB-231, MDA-MB-468, and MCF/Dox. NIS expression was studied by immunocytochemical method. Results: The strongest iodine symporter expression (248 ± 1.9; 272 ± 3.2 and 289 ± 2.8 points, respectively) were found in cells of highly malignant cell lines — MDA-MB-231, MDA-MB-468, and MCF-7/Dox. NIS expression was significantly weaker (< 120 points) in two BC cell lines of low malignancy (MCF-7 and T47D). In addition, the reduced sensitivity to Dox is associated with elevation of NIS expression in both high and low malignant cells. We have demonstrated correlations between NIS levels and certain indices of BC malignancy, namely proliferative activity (r = 0.51), receptor status (estrogen receptor; r = –0.47; and progesteron receptor; r = –0.47) and invasiveness (r = 0.46). Conclusions: Our data evidence that NIS expression level correlates with BC cells indices of malignancy and their sensitivity to Dox. The results obtained suggest the necessity for further studies of NIS expression in BC patients aimed at prognosing disease course and monitoring treatment efficacy with anthracyclines. 2016 Article Correlation of iodine symporter expression in highly and low malignant cell lines of human breast cancer differed in their sensitivity to doxorubicin / N.Yu. Lukianova, A.V. Andriiv, V.F. Chekhun // Experimental Oncology. — 2016 — Т. 38, № 3. — С. 169-171. — Бібліогр.: 18 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/137741 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Original contributions Original contributions Lukianova, N.Yu. Andriiv, A.V. Chekhun, V.F. Correlation of iodine symporter expression in highly and low malignant cell lines of human breast cancer differed in their sensitivity to doxorubicin Experimental Oncology |
| description |
Aim: To investigate the relationship of sodium/iodide symporter (NIS) expression with molecular phenotype of highly and low malignant cell lines of human breast cancer (BC) with different sensitivity to doxorubicin (Dox). Materials and Methods: The cell lines used in the analysis included T47D, MCF-7, MDA-MB-231, MDA-MB-468, and MCF/Dox. NIS expression was studied by immunocytochemical method. Results: The strongest iodine symporter expression (248 ± 1.9; 272 ± 3.2 and 289 ± 2.8 points, respectively) were found in cells of highly malignant cell lines — MDA-MB-231, MDA-MB-468, and MCF-7/Dox. NIS expression was significantly weaker (< 120 points) in two BC cell lines of low malignancy (MCF-7 and T47D). In addition, the reduced sensitivity to Dox is associated with elevation of NIS expression in both high and low malignant cells. We have demonstrated correlations between NIS levels and certain indices of BC malignancy, namely proliferative activity (r = 0.51), receptor status (estrogen receptor; r = –0.47; and progesteron receptor; r = –0.47) and invasiveness (r = 0.46). Conclusions: Our data evidence that NIS expression level correlates with BC cells indices of malignancy and their sensitivity to Dox. The results obtained suggest the necessity for further studies of NIS expression in BC patients aimed at prognosing disease course and monitoring treatment efficacy with anthracyclines. |
| format |
Article |
| author |
Lukianova, N.Yu. Andriiv, A.V. Chekhun, V.F. |
| author_facet |
Lukianova, N.Yu. Andriiv, A.V. Chekhun, V.F. |
| author_sort |
Lukianova, N.Yu. |
| title |
Correlation of iodine symporter expression in highly and low malignant cell lines of human breast cancer differed in their sensitivity to doxorubicin |
| title_short |
Correlation of iodine symporter expression in highly and low malignant cell lines of human breast cancer differed in their sensitivity to doxorubicin |
| title_full |
Correlation of iodine symporter expression in highly and low malignant cell lines of human breast cancer differed in their sensitivity to doxorubicin |
| title_fullStr |
Correlation of iodine symporter expression in highly and low malignant cell lines of human breast cancer differed in their sensitivity to doxorubicin |
| title_full_unstemmed |
Correlation of iodine symporter expression in highly and low malignant cell lines of human breast cancer differed in their sensitivity to doxorubicin |
| title_sort |
correlation of iodine symporter expression in highly and low malignant cell lines of human breast cancer differed in their sensitivity to doxorubicin |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2016 |
| topic_facet |
Original contributions |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/137741 |
| citation_txt |
Correlation of iodine symporter expression in highly and low malignant cell lines of human breast cancer differed in their sensitivity to doxorubicin / N.Yu. Lukianova, A.V. Andriiv, V.F. Chekhun // Experimental Oncology. — 2016 — Т. 38, № 3. — С. 169-171. — Бібліогр.: 18 назв. — англ. |
| series |
Experimental Oncology |
| work_keys_str_mv |
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| first_indexed |
2025-07-10T02:38:43Z |
| last_indexed |
2025-07-10T02:38:43Z |
| _version_ |
1837225870950924288 |
| fulltext |
Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ���
CORRELATION OF IODINE SYMPORTER EXPRESSION IN HIGHLY
AND LOW MALIGNANT CELL LINES OF HUMAN BREAST CANCER
DIFFERED IN THEIR SENSITIVITY TO DOXORUBICIN
N.Yu. Lukianova1,*, A.V. Andriiv2,3, V.F. Chekhun1
1R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv 03022, Ukraine
2Ivano-Frankivsk Regional Clinical Cancer Center, Ivano-Frankivsk 76018, Ukraine
3Ivano-Frankivsk National Medical University, Ivano-Frankivsk 76018, Ukraine
Aim: To investigate the relationship of sodium/iodide symporter (NIS) expression with molecular phenotype of highly and low malig-
nant cell lines of human breast cancer (BC) with different sensitivity to doxorubicin (Dox). Materials and Methods: The cell lines used
in the analysis included T47D, MCF-7, MDA-MB-231, MDA-MB-468, and MCF/Dox. NIS expression was studied by immuno-
cytochemical method. Results: The strongest iodine symporter expression (248 ± 1.9; 272 ± 3.2 and 289 ± 2.8 points, respectively)
were found in cells of highly malignant cell lines — MDA-MB-231, MDA-MB-468, and MCF-7/Dox. NIS expression was signifi-
cantly weaker (< 120 points) in two BC cell lines of low malignancy (MCF-7 and T47D). In addition, the reduced sensitivity to Dox
is associated with elevation of NIS expression in both high and low malignant cells. We have demonstrated correlations between NIS
levels and certain indices of BC malignancy, namely proliferative activity (r = 0.51), receptor status (estrogen receptor; r = –0.47;
and progesteron receptor; r = –0.47) and invasiveness (r = 0.46). Conclusions: Our data evidence that NIS expression level correlates
with BC cells indices of malignancy and their sensitivity to Dox. The results obtained suggest the necessity for further studies of NIS
expression in BC patients aimed at prognosing disease course and monitoring treatment efficacy with anthracyclines.
Key Words: sodium/iodide symporter, breast cancer, malignancy, sensitivity to doxorubicin.
Recent studies in �reast cancer �BC� indicate
su�stantial varia�ility of morphological variants and
molecular profile as well as disease course and
response to treatment [�� �]. High heterogeneity
and pathogenetic diversity of BC make crucial their
molecular chara cterization �ased on new �iological
markers [�]. The special attention should �e paid to the
studies of the role of iodine meta�olism distur�ances
in BC occurrence and progression [4]. The pro�lem
of the possi�le linkage �etween the impairments
of iodine and the BC occurrence has �een discussed
repeatedly over many decades� and still remains con-
troversial [5]. �ingle clinical o�servations showed that
the BC incidence is very low in those regions where
endemic goiter is rare.
�odium/iodide symporter �NI�� is a glycoprotein
that is integrated into the �asolateral cell surface;
it contains �� transmem�rane domains� and is es-
sential component for the thyroid hormones �iosyn-
thesis [�]. It is noteworthy� that NI� is a�le to function
as iodine transporter only under conditions of its mem-
�rane localization. When the protein translocates from
mem�rane to cytoplasm� which is typical for certain
pathological conditions� it loses its functional activity
and does not provide iodine a�sorption �y cells from
microvasculature [�]. It is known that functional NI�
activity depends on various factors: thyroid stimulat-
ing hormones� sex hormones� cytokines� transcrip-
tional and growth factors etc. The majority of research
is devoted to the NI� activity studies in differentiated
thyroid carcinoma. Recently� NI� was detected in the
cells of hormone-dependent tumors� including pros-
tate and BC. According to the literature data the NI�
expression is o�served in more than 5�% of malignant
�reast tumors [�]. There are some papers on cor-
relation �etween NI� transcriptional activity� tumor
receptor status and expression of epidermal growth
factor receptor with tyrosine kinase activity. However�
the specific evidence of this relationship is a�sent� and
the NI� expression in BC cells with varying sensitivity
to anthracycline cytotoxic drugs remains unclear.
The aim — to investigate the relationship of NI�
expression with molecular phenotype features of hu-
man BC cells and to clarify participation of this protein
in the determination of sensitivity to doxoru�icin �Dox�.
MATERIALS AND METHODS
Cell lines and drug treatment. The studies were
performed in vitro on 5 human BC cell lines: T4�D —
metastatic �reast ductal carcinoma; MDA-MB-��� and
MDA-MB-4�� — metastatic �reast adenocarcinoma;
MCF-� — invasive �reast ductal carcinoma; MCF-�/
Dox — its variant� resistant to Dox.
T4�D cells were cultured in RPMI-��4� medium ��ig-
ma� U�A� supplemented with �ovine insulin ��.� U/ml�
and ��% fetal �ovine serum �FB��. MCF-� cells were
grown in DMEM ��igma� U�A� supplemented with
recom�inant human insulin ��.�� mg/ml� and ��%
FB�. MDA-MB-��� and MDA-MB-4�� cells were
cultured in Lei�ovitz’s L-�5 medium ��igma� U�A�
supplemented with ��% FB�. All cultures were grown
on glass cover slips in humidified atmosphere with 5%
CO� at �� °C. The resistant variant MCF-�/Dox were
originated �y growing parental MCF-� cells with rising
Dox concentrations �from �.� to �� µg/ml�� respectively.
Submitted: August 20, 2016.
*Correspondence: E-mail: lu_na@rambler.ru
Abbreviations used: BC — breast cancer; Dox — doxorubicin;
NIS — sodium/iodide symporter.
Exp Oncol ����
��� �� �������
ORIGINAL CONTRIBUTIONS
��� Experimental Oncology ��� �������� ���� ��eptem�er�
Dox were added twice a week after reseeding. Every
� months� cell survival rate was analyzed �y MTT as-
say. MCF-�/Dox cells were �� times as much resistant
to the cytotoxic effect of Dox as parental MCF-� cells.
The cell lines were o�tained from the Bank of Cell Lines
from Human and Animal Tissues of the R.E. Kavetsky
Institute of Experimental Pathology� Oncology and
Radio�iology �IEPOR� of the National Academy of �ci-
ences of Ukraine.
The high or low malignant phenotype was evaluated
taking into account receptor status� proliferation activ-
ity and invasive properties [�]. MDA-MB-���� MDA-
MB-4�� and MCF-�/Dox cells were considered highly
malignant �a�sence of steroid hormone receptors�
high invasive potential and low adhesive properties�.
T4�D and MCF-� cells were considered low malignant
�high expression of estrogen and progesterone recep-
tors� low invasive activity�.
The sensitivity to Dox of explored cell lines was
measured �y IC�� and IC5�. For assessment of NI� ex-
pression changes caused �y Dox in studied cell lines�
the cells were incu�ated with the cytostatic at doses
that corresponded to IC��.
Immunocytochemical assay. The cells were
fixed on cover slips �in triplicate for each sample�
in ice-cold methanol:acetone ��:�� at −�� °C for
��� min and incu�ated with �% �ovine serum al�umin
solution for �� min. For immunocytochemical assay
primary аnti-NI� monoclonal anti�ody �Clone FP5A�
��:�5�� �Thermo �cientific� U�A� was used. UltraVision
LP Detection �ystem �La� Vision� Thermo �cientific�
U�A� and DAB Quanto �Thermo �cientific� were used
according to the instructions of the manufacturers.
When immunocytochemical reaction was completed�
the cells were stained with haematoxylin �y Mayer
and placed in Faramount Aqueous Mounting Medium
�DakoCytomation� Denmark�. Results were analyzed
�y light microscopy �× ����� oil immersion� with the
use of classical H-�core method:
S = 1 • N1+ + 2 • N2+ + 3 • N3+,
where � — «H-�core» index� N�+� N�+ and N�+ —
num�er of cells with low� medium or high marker ex-
pression [��]. The level of studied markers expression
was assigned as follows: low — from � to ��� H-score
points� medium — from ��� to ��� H-score points� and
high — from ��� to ��� H-score points.
Statistical analysis. �TATI�TIСA �.� computer
program ��tat�oft Inc.� U�A� was used for statisti-
cal processing of the o�tained results. Differences
�etween the average values were compared with use
of �tudent’s t-test; correlation analysis was performed
using Pearson correlation coefficient. Differences were
considered as significant with the pro�a�ility not less
than �5% �р < �.�5�.
RESULTS AND DISCUSSION
As seen from the data presented in Ta�le �� two
of three highly malignant cell lines used in the study�
namely MDA-MB-4�� and MCF-�/Dox high were
Dox resistant. Two low malignant cell lines �T4�D
and MCF-�� and one highly malignant cell line
�MDA-MB-���� were sensitive to Dox.
Table 1. The level of sensitivity of BC cells to Dox
Cell lines and their
malignancy
Inhibitory concentration of Dox
IC30 IC50
T47D low (n = 3) 0.9 1.5
MCF-7 low (n = 3) 1.5 2.5
MDA-MB-231 high (n = 3) 1.8 3.0
MDA-MB-468 high (n = 3) 6.0 10.0
MCF-7/Dox high (n = 3) 15.0 25.0
Immunocytochemical analysis revealed different
NI� expression in studied cells lines. The highest values
of iodine symporter expression ��4� ± �.�; ��� ± �.� and
��� ± �.� points� respectively� were found in highly malig-points� respectively� were found in highly malig-� respectively� were found in highly malig-respectively� were found in highly malig-� were found in highly malig-were found in highly malig- found in highly malig-found in highly malig- in highly malig-in highly malig- highly malig-highly malig-
nant cell lines MDA-MB-���� MDA-MB-4�� and MCF-�/
Dox �Ta�le ��. NI� expression was significantly weaker
�<��� points� in two low malignant cell lines �MCF-� and
T4�D�. In Dox-resistant variant of MCF-� cells �MCF-�/
Dox�� NI� expression was �.5 times as much as in pa-�� NI� expression was �.5 times as much as in pa-
rental MCF-� cell line �see Ta�le ��.
Table 2. NIS expression in BC cells of different malignancy and sensitivity
to Dox
Cell line Malignancy
features
Sensitivity
to Dox
NIS expression level
(H-score, points)
T47D Low High 73.0 ± 2.0
MCF-7 Low High 115.0 ± 1.9
MDA-MB-231 High High 248.0 ± 2.6*
MDA-MB-468 High Middle 272.0 ± 2.5*
MCF-7/Dox High Low 289.0 ± 2.8*,#
Note: *p < 0.05 in comparison with low malignant cells; #p < 0.05 in com- < 0.05 in com-< 0.05 in com- 0.05 in com-0.05 in com-in com-
parison with cells of parental MCF-7 line.
�ince we know that NI� is a�le to transport iodine
only when it is expressed on cells mem�ranes [��� ��]�
we attempted to analyze NI� localization in studied
cells lines. In low malignant cell �T4�D and MCF-���
NI� expressed �oth on mem�rane and in cytoplasm�
�ut in highly malignant cell lines� the cytoplasmic
reaction with anti�odies against this protein prevailed
�Fig. ��. It should �e noted that in MCF-�/Dox cells NI�
relocalized to cytoplasm as compared to the parental
MCF-� cell line �see Fig. ��. Therefore� in highly ma-cell line �see Fig. ��. Therefore� in highly ma-�see Fig. ��. Therefore� in highly ma-see Fig. ��. Therefore� in highly ma-. ��. Therefore� in highly ma- ��. Therefore� in highly ma-��. Therefore� in highly ma- Therefore� in highly ma-
lignant cell lines� Dox resistance is accompanied with
NI� relocalization.
0
20
40
60
80
100
T47D MCF-7 MDA-MB-231 MDA-MB-468 MCF-7/Dox
Su
bc
el
lu
la
r d
is
tri
bu
tio
n,
%
Membrane
Cytoplasm
Fig. 1. �u�cellular distri�ution of NI� in BC cells of different
malignancy and sensitivity to Dox
The analysis of correlations allowed us to de- analysis of correlations allowed us to de-analysis of correlations allowed us to de- of correlations allowed us to de-of correlations allowed us to de- correlations allowed us to de-correlations allowed us to de- allowed us to de-allowed us to de- us to de-us to de-
termine the relations of NI� expression with some
indices of BC malignancy. Increase in NI� expression
was associated with the lack of steroid hormones
receptors in highly malignant cells and in cells with
phenotype of chemoresistance to Dox �Ta�le ��. The
Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ���
direct correlation �etween NI� expression and indices
of proliferative activity in cells of low malignancy was
o�served �see Ta�le ��. We proved the association
of NI� level with invasive properties of low malignant
cells and MCF-�/Dox cells �see Ta�le ��. The a�ove
data confirm the NI� participation in the formation
of BC cells molecular phenotype.
Table 3. Correlation between NIS expression and indices of malignancy
of BC cells
Indices Correlation coefficients
Low malignancy High malignancy Resistance to Dox
NIS/estrogen receptors −0.47* −0.49* −0.61*
NIS/progesteron
receptors −0.43* −0.49* −0.58*
NIS/Ki-67 0.51* 0.25 0.22
NIS/invasiveness 0.46* 0.19 0.54*
Note: *p < 0.05.
In cell cultures supplementation with Dox� marked
reduction in NI� expression was o�served in T4�D
and MCF-� cell lines ��y �� and 4�%� respectively��
that are characterized �y high sensitivity to this cy-
tostatic drug and in MDA-MB-��� line ��y ��.�%�
�Fig. ��. �upplementation with Dox did not affect NI�
level in Dox-resistant MDA-MB 4�� and MCF-�/Dox
cell lines. These data strongly suggest the role of NI�
in realization of cytostatics effects of Dox.
0
50
100
150
200
250
300
T47D MCF-7 MDA-MB-231 MDA-MB-468 MCF-7/Dox
NI
S
ex
pr
es
si
on
le
ve
ls
(H
-S
co
re
, p
oi
nt
s)
Control
Dox
Fig. 2. NI� expression shifts in human BC cells caused �y Dox
We found the correlations �etween NI� expres-
sion and malignant phenotype as well Dox resistance
in human BC cell lines. The highest NI� expression
was demonstrated in high malignant cell lines resis-
tant to Dox. Our results coincide with pu�lished data
on correlations �etween NI� levels and certain indices
of BC malignancy� namely proliferative activity� recep-
tor status and invasiveness [����5]. The data o�tained
indicate that elevated NI� level and its su�cellular
relocalization are associated with the lack expres-
sion of steroid hormone receptors� high proliferative
activity and invasiveness of BC cells. These features
may �e associated with the reduced iodine a�sorption
�y highly malignant cells as the consequence of altered
NI� functional activity [��]. The detected relationship
�etween NI� level and sensitivity of human BC cells
to Dox allows one to suggest NI� participation in the
mechanisms of realization of Dox cytostatic effects.
The significant shifts of NI� expression that we found
in cells with Dox-resistant phenotype are pro�a�ly due
to the MDR1 gene activation [��� ��].
To sum up� our data demonstrate that NI� expres-� our data demonstrate that NI� expres-our data demonstrate that NI� expres- data demonstrate that NI� expres-data demonstrate that NI� expres- demonstrate that NI� expres-demonstrate that NI� expres- that NI� expres-that NI� expres- NI� expres-NI� expres- expres-expres-
sion level correlates with BC cells indices of malig- level correlates with BC cells indices of malig-level correlates with BC cells indices of malig- correlates with BC cells indices of malig-correlates with BC cells indices of malig- with BC cells indices of malig-with BC cells indices of malig- BC cells indices of malig-BC cells indices of malig- cells indices of malig-cells indices of malig- indices of malig-indices of malig- of malig-of malig- malig-malig-
nancy as well Dox resistance in human BC cell lines.
Further studies of NI� expression in BC patients seem
to �e advantageous for predicting the disease course
and monitoring treatment efficacy with antracyclines.
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