Lactoferrin expression in breast cancer in relation to biologic properties of tumors and clinical features of disease
Aim: To determine the patterns of lactoferrin (LF) expression in breast cancer (BC) in relation to biologic properties of the neoplasms and clinical features of the disease course. Materials and Methods: Clinical specimens of 266 BC patients (115 patients with BC of stages I–II — retrospective study...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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| Zitieren: | Lactoferrin expression in breast cancer in relation to biologic properties of tumors and clinical features of disease / L.A. Naleskina, N.Yu. Lukianova, S.O. Sobchenko, D.M. Storchai, V.F. Chekhun // Experimental Oncology. — 2016 — Т. 38, № 3. — С. 181-186. — Бібліогр.: 35 назв. — англ. |
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irk-123456789-1377312018-06-18T03:05:29Z Lactoferrin expression in breast cancer in relation to biologic properties of tumors and clinical features of disease Naleskina, L.A. Lukianova, N.Yu. Sobchenko, S.O. Storchai, D.M. Chekhun, V.F. Original contributions Aim: To determine the patterns of lactoferrin (LF) expression in breast cancer (BC) in relation to biologic properties of the neoplasms and clinical features of the disease course. Materials and Methods: Clinical specimens of 266 BC patients (115 patients with BC of stages I–II — retrospective study, and 151 BC patients — prospective study) were analyzed. Morphological, immunohistochemical and statistical methods were used. Results: The number of LF-positive tumors in retrospective and prospective groups was similar (52.1 and 52.8%, respectively). Among common clinical criteria for prognosis of the disease outcome in BC patients (patient’s age; stage of the disease; histological type, differentiation grade, receptor status; presence of metastases), a strong correlation was found only between expression indexes of LF and estrogen receptors (ER). In ER-positive tumors expression of LF was significantly higher than in ER-negative tumors (35 vs 18%). 5-Year survival rate of BC patients was higher in LF-positive group (70 vs 52% in LF-negative group). The presence of regional metastasis tended to correlate with an increased number of LF-positive tumors. In the patients with invasive ductal carcinoma, expression level of LF moderately correlated with occurrence of luminal A subtype (r = 0.43), while in the patients with invasive lobular carcinoma this index strongly correlated with occurrence of luminal B subtype (r = 0.71). LF expression correlated positively with low and moderate differentiation grade of luminal B or basal tumors, and negatively with luminal B or basal tumors of high differentiation grade (r = −0.57 and −0.63, respectively). Conclusion: It has been shown that LF expression in breast tumors correlated with life expectancy of BC patients and important physiologic and clinical features of the disease, while the character of such relation strongly depended on molecular phenotype of tumor, i.e. luminal A, luminal B or basal. 2016 Article Lactoferrin expression in breast cancer in relation to biologic properties of tumors and clinical features of disease / L.A. Naleskina, N.Yu. Lukianova, S.O. Sobchenko, D.M. Storchai, V.F. Chekhun // Experimental Oncology. — 2016 — Т. 38, № 3. — С. 181-186. — Бібліогр.: 35 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/137731 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Original contributions Original contributions Naleskina, L.A. Lukianova, N.Yu. Sobchenko, S.O. Storchai, D.M. Chekhun, V.F. Lactoferrin expression in breast cancer in relation to biologic properties of tumors and clinical features of disease Experimental Oncology |
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Aim: To determine the patterns of lactoferrin (LF) expression in breast cancer (BC) in relation to biologic properties of the neoplasms and clinical features of the disease course. Materials and Methods: Clinical specimens of 266 BC patients (115 patients with BC of stages I–II — retrospective study, and 151 BC patients — prospective study) were analyzed. Morphological, immunohistochemical and statistical methods were used. Results: The number of LF-positive tumors in retrospective and prospective groups was similar (52.1 and 52.8%, respectively). Among common clinical criteria for prognosis of the disease outcome in BC patients (patient’s age; stage of the disease; histological type, differentiation grade, receptor status; presence of metastases), a strong correlation was found only between expression indexes of LF and estrogen receptors (ER). In ER-positive tumors expression of LF was significantly higher than in ER-negative tumors (35 vs 18%). 5-Year survival rate of BC patients was higher in LF-positive group (70 vs 52% in LF-negative group). The presence of regional metastasis tended to correlate with an increased number of LF-positive tumors. In the patients with invasive ductal carcinoma, expression level of LF moderately correlated with occurrence of luminal A subtype (r = 0.43), while in the patients with invasive lobular carcinoma this index strongly correlated with occurrence of luminal B subtype (r = 0.71). LF expression correlated positively with low and moderate differentiation grade of luminal B or basal tumors, and negatively with luminal B or basal tumors of high differentiation grade (r = −0.57 and −0.63, respectively). Conclusion: It has been shown that LF expression in breast tumors correlated with life expectancy of BC patients and important physiologic and clinical features of the disease, while the character of such relation strongly depended on molecular phenotype of tumor, i.e. luminal A, luminal B or basal. |
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Article |
| author |
Naleskina, L.A. Lukianova, N.Yu. Sobchenko, S.O. Storchai, D.M. Chekhun, V.F. |
| author_facet |
Naleskina, L.A. Lukianova, N.Yu. Sobchenko, S.O. Storchai, D.M. Chekhun, V.F. |
| author_sort |
Naleskina, L.A. |
| title |
Lactoferrin expression in breast cancer in relation to biologic properties of tumors and clinical features of disease |
| title_short |
Lactoferrin expression in breast cancer in relation to biologic properties of tumors and clinical features of disease |
| title_full |
Lactoferrin expression in breast cancer in relation to biologic properties of tumors and clinical features of disease |
| title_fullStr |
Lactoferrin expression in breast cancer in relation to biologic properties of tumors and clinical features of disease |
| title_full_unstemmed |
Lactoferrin expression in breast cancer in relation to biologic properties of tumors and clinical features of disease |
| title_sort |
lactoferrin expression in breast cancer in relation to biologic properties of tumors and clinical features of disease |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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2016 |
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Original contributions |
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http://dspace.nbuv.gov.ua/handle/123456789/137731 |
| citation_txt |
Lactoferrin expression in breast cancer in relation to biologic properties of tumors and clinical features of disease / L.A. Naleskina, N.Yu. Lukianova, S.O. Sobchenko, D.M. Storchai, V.F. Chekhun // Experimental Oncology. — 2016 — Т. 38, № 3. — С. 181-186. — Бібліогр.: 35 назв. — англ. |
| series |
Experimental Oncology |
| work_keys_str_mv |
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| first_indexed |
2025-07-10T02:38:24Z |
| last_indexed |
2025-07-10T02:38:24Z |
| _version_ |
1837225850418757632 |
| fulltext |
Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ���
LACTOFERRIN EXPRESSION IN BREAST CANCER IN RELATION
TO BIOLOGIC PROPERTIES OF TUMORS AND CLINICAL FEATURES
OF DISEASE
L.A. Naleskina, N.Yu. Lukianova*, S.O. Sobchenko, D.M. Storchai, V.F. Chekhun
R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv, Ukraine
Aim: To determine the patterns of lactoferrin (LF) expression in breast cancer (BC) in relation to biologic properties of the neoplasms
and clinical features of the disease course. Materials and Methods: Clinical specimens of 266 BC patients (115 patients with
BC of stages I–II — retrospective study, and 151 BC patients — prospective study) were analyzed. Morphological, immunohisto-
chemical and statistical methods were used. Results: The number of LF-positive tumors in retrospective and prospective groups was
similar (52.1 and 52.8%, respectively). Among common clinical criteria for prognosis of the disease outcome in BC patients (pa-
tient’s age; stage of the disease; histological type, differentiation grade, receptor status; presence of metastases), a strong correlation
was found only between expression indexes of LF and estrogen receptors (ER). In ER-positive tumors expression of LF was signifi-
cantly higher than in ER-negative tumors (35 vs 18%). 5-Year survival rate of BC patients was higher in LF-positive group (70 vs 52%
in LF-negative group). The presence of regional metastasis tended to correlate with an increased number of LF-positive tumors. In the
patients with invasive ductal carcinoma, expression level of LF moderately correlated with occurrence of luminal A subtype (r = 0.43),
while in the patients with invasive lobular carcinoma this index strongly correlated with occurrence of luminal B subtype (r = 0.71).
LF expression correlated positively with low and moderate differentiation grade of luminal B or basal tumors, and negatively with
luminal B or basal tumors of high differentiation grade (r = −0.57 and −0.63, respectively). Conclusion: It has been shown that
LF expression in breast tumors correlated with life expectancy of BC patients and important physiologic and clinical features of the
disease, while the character of such relation strongly depended on molecular phenotype of tumor, i.e. luminal A, luminal B or basal.
Key Words: lactoferrin, breast cancer, molecular phenotype, estrogen receptors, prognosis of the disease course.
Breast cancer �BC� is the most prevalent oncologic
pathology in women. It is �elieved that an effectiveness
of therapy of this disease could �e improved �y the de-
velopment of new means for �iologic correction of iron
homeostasis as an important factor of sta�le functioning
of all �ody systems. New knowledge a�out the role of iron
in the development and progression of tumors has �een
gained due to the studies of the intracellular content and
tissue distri�ution of iron-containing proteins and their
receptors.
It is known that at cellular and molecular levels
the regulation of iron meta�olism is exerted through the
�alanced action of iron-containing proteins� including
transporter proteins. Transport of iron in a protein-�ound
form minimi�es its capa�ility for participation in the reac- minimi�es its capa�ility for participation in the reac-minimi�es its capa�ility for participation in the reac- its capa�ility for participation in the reac-its capa�ility for participation in the reac- capa�ility for participation in the reac-capa�ility for participation in the reac- for participation in the reac-for participation in the reac- participation in the reac-participation in the reac- in the reac-in the reac- the reac-the reac- reac-reac-
tions of free-radical oxidation� and therefore decreases
possi�le oxidative damage of cells and tissues of an or- oxidative damage of cells and tissues of an or-oxidative damage of cells and tissues of an or- damage of cells and tissues of an or-damage of cells and tissues of an or- of cells and tissues of an or-of cells and tissues of an or- cells and tissues of an or-cells and tissues of an or- and tissues of an or-and tissues of an or- tissues of an or-tissues of an or- of an or-of an or- an or-an or- or-or-
ganism [�].
While the meta�olic patterns of such iron-containing
proteins as ferritin� transferrin� ferroportin in BC patients
are studied in detail [�]� the role of lactoferrin ���� in patho- studied in detail [�]� the role of lactoferrin ���� in patho-studied in detail [�]� the role of lactoferrin ���� in patho- in detail [�]� the role of lactoferrin ���� in patho-in detail [�]� the role of lactoferrin ���� in patho- detail [�]� the role of lactoferrin ���� in patho-detail [�]� the role of lactoferrin ���� in patho-[�]� the role of lactoferrin ���� in patho-� the role of lactoferrin ���� in patho- the role of lactoferrin ���� in patho-the role of lactoferrin ���� in patho- role of lactoferrin ���� in patho-role of lactoferrin ���� in patho- of lactoferrin ���� in patho-of lactoferrin ���� in patho- lactoferrin ���� in patho-in patho- patho-patho-
genesis� clinical course and prognosis of BC is still poorly
understood. �� is an iron-�inding glycoprotein of trans-. �� is an iron-�inding glycoprotein of trans-is an iron-�inding glycoprotein of trans- an iron-�inding glycoprotein of trans-an iron-�inding glycoprotein of trans- iron-�inding glycoprotein of trans-iron-�inding glycoprotein of trans--�inding glycoprotein of trans-�inding glycoprotein of trans- glycoprotein of trans-glycoprotein of trans- of trans-of trans-
ferrin family of iron transporter proteins� with a molecular
weight of 7�.� kD composed of a single polypeptide
chain. �� contains 7�� aminoacids and forms two ho-. �� contains 7�� aminoacids and forms two ho-�� contains 7�� aminoacids and forms two ho- contains 7�� aminoacids and forms two ho-contains 7�� aminoacids and forms two ho- 7�� aminoacids and forms two ho-aminoacids and forms two ho- forms two ho-forms two ho- two ho-two ho- ho-ho-
mological domains� N- and C-parts of which contain
an iron-�inding center and have a special function [�].
Different �� isoforms have �een identified. ��-� is ca- �� isoforms have �een identified. ��-� is ca- isoforms have �een identified. ��-� is ca- ��-� is ca-is ca- ca-ca-
pa�le to �ind iron ions �ut has no ri�onuclease activity
while isoforms ��-β and -γ exert ri�onuclease activity �ut
are incapa�le to �ind metal ions [4]. Apart from this� the
protein could exist in iron-saturated form �hololactoferrin�
or iron-unsaturated form �apolactoferrin�. One molecule
of the protein could �e �ound with two ions of iron� cop- the protein could �e �ound with two ions of iron� cop-the protein could �e �ound with two ions of iron� cop- protein could �e �ound with two ions of iron� cop-protein could �e �ound with two ions of iron� cop- could �e �ound with two ions of iron� cop-could �e �ound with two ions of iron� cop- �e �ound with two ions of iron� cop-�e �ound with two ions of iron� cop- �ound with two ions of iron� cop-�ound with two ions of iron� cop- with two ions of iron� cop-with two ions of iron� cop- two ions of iron� cop-two ions of iron� cop- ions of iron� cop-ions of iron� cop- of iron� cop-of iron� cop- iron� cop-iron� cop-� cop-cop-
per� �inc or other metals.
Also it has �een shown that some functional features
of �� depend on its oligomeric state. As a monomer�
�� is capa�le to �ind with DNA and regulate granulo-
poiesis� while tetrameric form of �� lacks such fea-�� lacks such fea-lacks such fea-
tures [5]. It has �een esta�lished that the process
of conformational rearrangement of �� with formation
of mono-� di-� tri-� or tetrameric forms requires adenosine
triphosphate [�].
In adult human �ody� �� is stored in neutrophils�
specific �secondary� granules of which contain large
amounts of ��. �� content may vary depending on gen-��. �� content may vary depending on gen-content may vary depending on gen-
der and age� however� the results of different studies
are contradictory. After degranulation of neutrophils�
�� is released into the �lood and is quickly �ound to and
a�sor�ed �y parenchymatous cells of liver and spleen.
Under normal conditions� �lood plasma �� concentra-�� concentra-concentra-
tion is �.4��.� mg/l. There are some data on significant
elevation of �� content in �iological fluids �up to ��� mg/l�
upon some pathologies� including cancer� and especially
upon inflammatory states� therefore �� content could
�e used as a �iochemical marker of inflammation [7].
An important feature of �� is its capa�ility to �ind
with nucleic acids� especially with dou�le-stranded
DNA. �� is internali�ed with participation of �� recep-. �� is internali�ed with participation of �� recep-is internali�ed with participation of �� recep-
tor along with iron ions �ound with its molecule. Also�
Submitted: August 16, 2016.
*Correspondence: E-mail: lu_na_u@rambler.ru
Abbreviations used: BC — breast cancer; ER — estrogen receptor;
LF — lactoferrin; PR — progesteron receptor.
Exp Oncol ����
��� �� �������
��� Experimental Oncology ��� �������� ���� ��eptem�er�
�� regulates the concentration of iron ions in �lood and
secretory fluids� exerts antimicro�ial and antiviral action
and is considered as an important immune factor of milk.
It directly participates in defense reactions of a �ody
and mediates the development of cellular immunity.
�� interacts with polyamines and heparin. Apart from this�
�� exerts antioxidant� immunomodulating and anticancer
activities [�]. �� is capa�le to enter cell nuclei and activate
transcription of specific genes� �ut such target genes
have not �een yet identified.
Therefore� �� is a protein with a wide spectrum of �io-
logic functions. The role of �� in the clinical course of BC re-. The role of �� in the clinical course of BC re-The role of �� in the clinical course of BC re-�� in the clinical course of BC re-in the clinical course of BC re-
mains unclear. There are a few stu dies of �� in BC cells
in vitro� in particular� �� increases migration and invasion
of triple receptor-positive and receptor-negative BC cells
[9]. Also it has �een shown that �� isolated from cow
milk is capa�le to decrease the via�ility of human �reast
carcinosarcoma H�57�T cells and human ductal �reast
epithelial tumor T47D cells �y 47 and 54%� respectively�
and to induce �-fold increased apoptosis in these cells
[��]. The results of our studies have shown that exogenous
�� can modify the molecular profile and invasive properties
of cultured BC cells with different potential of malignancy�
including drug-resistant MC�-7/Cp and MC�-7/Dox cell
lines [��]. Other researchers have demonstrated that
recom�inant human �� variants affect the properties
of tumor cells in vitro in a way that could �e considered
antitumorigenic [��� ��].
Presently there are scarce or no data on the role
of �� in the pathogenesis of BC� relation �etween
�� content and clinical� morphological and molecular-
�iologic characteristics of BC at different stages of the
disease� as well as �� validity as prognostic criterion for
clinical course of BC. Therefore� the aim of the study
was to analy�e the patterns of �� expression in tumor
cells of BC patients taking into account their �iological
properties and clinical features of the disease.
MATERIALS AND METHODS
The clinical specimens of ��� BC patients was ana-��� BC patients was ana-was ana-
ly�ed [�4]. The assessment of prognostic value of �� for
the disease outcome was �ased on a retrospective
analysis of the data of ��5 BC patients stages I�II treated
in Kyiv Municipal Clinical Oncologic Center in ���5����7.
A prospective study of �5� BC patients treated in the
same clinics in ��������4 was aimed at an assessment
of the relation �etween �� expression in tumors of dif-expression in tumors of dif-in tumors of dif- tumors of dif-s of dif-
ferent molecular phenotype and clinical characteristics
of BC affecting the course of the disease. All patients
provide an informed written consent on the use of indi-
vidual clinical data for scientific purposes.
All patients received surgical treatment �quadrant-
or lumpectomy with regional lymph node dissection�
radical mastectomy �y Madden�. The patients with
BC of stages І�ІІ were not treated with neoadjuvant
therapy. Adjuvant polychemotherapy was performed:
CM� �cyclophosphamide� methotrexate� fluorouracyl��
CA� �cyclophosphamide� doxoru�icine� fluorouracyl��
4�� courses; radiotherapy on postoperative cicatrix
and the �one of regional metastases at a total dose
of 4��44 �y. The patients with positive expression of hor-4��44 �y. The patients with positive expression of hor-�y. The patients with positive expression of hor-. The patients with positive expression of hor-The patients with positive expression of hor-expression of hor-of hor-
mone receptors in removed tumor tissue were treated
with prolonged hormonal therapy �y standard scheme
�tamoxiphene� aromatase inhi�itors� depending on the
individual clinical data.
�eneral clinico-pathological characteristics of BC pa-
tients are presented in Ta�le �. As one may see� the pa-Ta�le �. As one may see� the pa-As one may see� the pa-
tients from �oth groups were of similar age� the majority
of them �eing at menopause. By histological structure�
the most common BC type was invasive ductal cancer
of moderate differentiation grade. By the data of molecu-
lar-�iologic study� luminal А su�type was diagnosed
in the majority of BC patients from �oth groups.
Table 1. Clinico-pathologic characteristics of BC patients
Indexes
Retrospective
group
Prospective
group
Number of patients
n % n %
Total number of patients 115 100 151 100
Average age, years 54.2 ± 3.1 56.5 ± 9.6
Age range, years 23–75 28–89
Active menstrual cycle 39 33.9 29 19.2
Menopause 76 66.1 122 80.8
Stage І (T1N0M0) 27 23.5 47 31.1
Stage ІІ (T2N1–2M0)
Т2а (T1N0M0)
Т2b (T2N1–2M0)
88
53
35
76.5
46.0
30.5
104
81
23
68.9
53.6
15.3
Invasive ductal carcinoma 86 74.8 101 66.9
Invasive lobular carcinoma 29 25.2 50 33.1
Differentiation grade G1 (high) 32 27.8 42 27.8
Differentiation grade G2 (moderate) 59 51.3 78 51.7
Differentiation grade G3 (low) 24 20.9 31 20.5
Molecular subtype
Luminal A 53 46.0 81 53.6
Luminal B 31 27.0 35 23.2
Basal 31 27.0 35 23.2
All patients were examined with the use of common
clinical and la�oratory methods in accordance with
the standards for diagnostics and therapy of cancer
patients approved �y the orders of Ministry of Health
No.�4� of �7.�7.�99� and No.554 of �7.�9.���7.
The stage of cancer was estimated according to Inter-
national TNM classification ������.
�or morphologic research� surgically removed tumor
specimens was fixed in ��% neutral formaline solution
and further treated �y standard histological method.
The preparations were prepared from paraffine �locks�
stained with hematoxylin and eosin� and examined using
light microscopy.
Immunohistochemical determination of �� expres-
sion in the tumors was performed with the use of standard
streptavidine-�iotine-peroxydase method on histological
slides prepared from paraffine �locks after their fixation
in ��% solution of neutral formaline. The 4�5 mm histo-
logic sections were placed on �uper �rost Plus slides
��ermany�. �urther procedures were performed �y rou-
tine technique. Anti-�� MoA�s �A�cam� U�A� were used
as primary anti�odies. Visuali�ation was done using
EnVision system �Dako��AB� system� Denmark�. After
detection of peroxydase activity� the slides were stained
with Mayer’s hematoxylin. Assessment of �� expression
was performed �y semiquantitative method. In each
histological preparation� �� expression was analy�ed
per ���� tumor cells� the num�er of immunopositive and
immunonegative cells was expressed in percents ac-
Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ���
counting for the degree of the marker expression �high�
moderate� strong�. If the num�er of immunopositive cells
was higher than ��%� �� expression was considered
as a strong positive one.
�or immunohistochemical study of other markers
we have used anti�odies against estrogen receptors
�ER� �clone �D5�� progesterone receptors �PR� �clone
PgR����� epidermal growth factor receptor HER�/neu
�clone c-er�B-��� proliferation marker ʳ-�7 �clone
MIB-�� from DakoСytomation� Denmark. Assessment
of expression of mentioned proteins in �reast tumors
was performed �y counting immunopositive cells using
H-�core method [�5]. Expression from � to ��� scores
was considered low� ������� — moderate� and > ��� —
high. In the study light microscope Primo �tar �Zeiss�
�ermany�� magnification ����4��� was used.
�tatistical analysis of the data was done with the use
of �TATI�TICA �.� program. The relation �etween the
indexes was assessed using Pearson’s coefficient� its
significance analy�ed with the use of χ² test.
RESULTS AND DISCUSSION
Immunohistochemical detection of �� in BC samples
revealed a positive ��-specific reaction in cytoplasm
of tumor cell in �oth groups of the patients. The num�er
of ��-positive ����� tumors in retrospective and pro- ��-positive ����� tumors in retrospective and pro-��-positive ����� tumors in retrospective and pro-
spective groups did not differ and at average was equal
to 5�.� and 5�.�%� respectively.
In BC patients from group �� �� expression indexes
were analy�ed in relation to a num�er of clinical charac-
teristics each of which affecting the clinical course of the
disease� in particular� age and menstrual function of the
patients� the stage of the disease� histological type of the
tumor� its differentiation grade and degree of malignancy�
metastasis in regional lymph nodes� receptor status
of tumor cells.
The results of correlation analysis evidenced
on an a�sence of the difference in the num�ers of ���
tumors dependent on the age of patients with preserved
reproductive function ��4 �4�.�%�� and patients at meno-��4 �4�.�%�� and patients at meno-and patients at meno- patients at meno-at meno-
pause �4� �45.4%��. No correlation was found �etween
�� expression in tumor� BC stage and histological type
of BC. There was o�served a tendency �etween an in-. There was o�served a tendency �etween an in-There was o�served a tendency �etween an in-
creased num�er of ��� tumors in the patients with high
differentiated BC ��9 �47.5%�� compared to these with
moderately differentiated tumors ��7 �4�.5%�� and low
differentiated BC ��7 �4�.4%��.
The num�er of ��� tumors ���%� tended to increase
if regional lymph node metastasis N� was present.
As far as receptor status of BC is considered as the
most important prognostic marker and an o�jective
criterion for hormonal therapy [��]� we have studied
a relation �etween an expression of ER in BC cells and
�� expression in tumor cells of these patients. Interes-
tingly� in ER-positive �ER�� tumors an expression level
of �� was found to �e significantly� nearly twice higher
��5%� than in ER-negative �ER−� tumors ���%� ��ig. ��.
According to the data of literature� regulation
of �� synthesis depends on histological type of the cells
producing this protein� while amount of �� synthesi�ed
in mammary gland is controlled �y prolactin� and its
synthesis in reproductive tissue is regulated �y estro-
gens [�7]. Also� it has �een reported that �� is a ligand
for specific receptors on cell surface� which are selective
for each histological type [��]. This o�servation could
possi�ly explain a high expression level of �� in RE� BC.
0
5
10
15
20
25
30
35
40
ER– ER+
LF
+
tu
m
or
s,
%
Fig. 1. �� expression in ER� and ER� �reast tumors
Also� we have studied whether �� expression
in BC tissue could �e related to survival time of BC pa-
tients� the most valid clinical criterion [�9]. An analysis
of Kaplan — Meyer’s curves for the groups of BC patients
with ��� or ��-negative ���−� tumors ��ig. �� has shown
that 5-year survival was higher in ��� group. We suppose
that higher �� levels could increase functional activity
of immune system� as it has �een detected in the case
of inflammation when increased �� levels are related
to antiinflammatory cytokines [��]. It could �e con-[��]. It could �e con-It could �e con-
sidered reasona�le as far as some researchers claim
common features of inflammation and cancer [��].
A relation �etween �� and antiinflammatory cytokines
has �een found in the studies of lymphoproliferative
diseases [��] and malignant melanoma [��]. �urther
studies of �� expression in BC tissue and its relation
to survival of BC patients are required.
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60
Cu
m
ul
at
ive
s
ur
viv
al
in
de
x,
%
Survival time, months
LF+ ER+
LF– ER–
Fig. 2. Overall survival of BC patients depending on �� and ER ex-
pression in tumor cells
Presently BC is considered as a complex pathology
with various �iologic su�types which differ in the causes
of development� clinical and molecular features� have dif-
ferent prognosis and require special therapeutic strate-
gies [�4� �5]. In recent years a classification of molecular
portraits of BC proposed �y Perou et al. [��] �ecame
popular� �ecause different molecular BC su�types
�luminal А and В� �asal� Her�� differ not only �y molecular
markers �ut also �y specific �iology� which is supported
��4 Experimental Oncology ��� �������� ���� ��eptem�er�
�y clinical o�servations [�7]. In particular� it has �een
shown that molecular su�type may serve as an inde-
pendent prognostic criterion and a prediction factor
of an effectiveness of the therapy [��].
In view of the foregoing� we attempted the pro-
spective study of the relation �etween �� expression
in tumors and clinical features of BC including molecular
phenotype of the tumors. �� expression was a�out the
same in the tumors of patients aged 4��5� and ����9�
i.e.� at premenopausal and postmenopausal periods
��ig. ��. Nevertheless� the percentage of ��� tumors
decreased in the group of BC patients aged 5����� i.e.
at menopause. The stage І and ІІ groups differed neither
�y H-score of �� positivity� nor �y the percentage of ���
tumors �Ta�le ��. In �oth groups �stage I and II� the tu-
mors with low �� expression were prevalent ��5.� and
5�.7%� respectively� �see Ta�le ��.
0
5
10
15
20
25
30
35
40
45
50
42–50 51–60 61–89
LF
+
tu
m
or
s,
%
Age, years
*
Fig. 3. Expression of �� depending on the age of BC patients and
menstrual function. *The difference is significant compared to other
groups �p < �.�5�
Table 2. Expression of LF in breast tumors of different histological type
and at different stage of the disease
Clinical indexes
Number
of patients
Expression patterns of LF
in breast tumors
n %
Total number
of LF+ cells
(by H-Score)
Number
of tumors
with low
LF ex-
pression,
%
Number
of tumors with
moderate and
high LF ex-
pression, %
Stage of the disease
І
ІІ
35
75
31.8
68.2
172.3 ± 16.7
174.5 ± 14.4
65.8
58.7
34.2
41.3
Histological type of the tumor
Invasive ductal
carcinoma
Invasive lobular
carcinoma
75
25
70.9
22.7
187.2 ± 16.5*
143.2 ± 18.3
55.12*
76.92*
44.87*
23.07
Note: *the difference is significant compared to invasive lobular carcinoma
(р < 0.05)
Comparison of �� expression in the tumors of dif- of �� expression in the tumors of dif-of �� expression in the tumors of dif- �� expression in the tumors of dif-in the tumors of dif- the tumors of dif-the tumors of dif- tumors of dif-s of dif- of dif-of dif- dif-dif-
ferent histological type revealed significantly higher
num�er of ��� cells in invasive ductal carcinoma
vs invasive lo�ular carcinoma �see Ta�le ��. In inva-invasive lo�ular carcinoma �see Ta�le ��. In inva- lo�ular carcinoma �see Ta�le ��. In inva-lo�ular carcinoma �see Ta�le ��. In inva- carcinoma �see Ta�le ��. In inva-carcinoma �see Ta�le ��. In inva- �see Ta�le ��. In inva-see Ta�le ��. In inva-Ta�le ��. In inva-��. In inva-�. In inva- In inva-
sive ductal carcinoma� the percent of the tumors with
moderate and high �� expression was significantly
higher than the percent of tumors with low �� expres-
sion �55.�� vs 44.�7%�. In invasive lo�ular carcinoma�
the tumors with low �� expression were prevalent
�7�.9� vs ��.�7%�. Also� it was shown that in the tu-.�7%�. Also� it was shown that in the tu-�7%�. Also� it was shown that in the tu-Also� it was shown that in the tu-� it was shown that in the tu-it was shown that in the tu- was shown that in the tu-was shown that in the tu- shown that in the tu-shown that in the tu- that in the tu-that in the tu- in the tu-in the tu- the tu-the tu- tu-tu-
mors of low differentiation grade� �� expression was
significantly higher than in the tumors of high or mo-
derate differentiation grade �Ta�le ��.
Table 3. Expression patterns of LF in breast tumors of different differentiation
grade
Differen-
tiation
grade
of the tu-
mor
Number of patients Expression patterns of LF in breast tumors
n %
Total number
of LF+ cells
(by H-Score)
Number
of tumors
with low
LF expres-
sion, %
Number
of tumors
with high
LF expres-
sion, %
High
Moderate
Low
22
57
32
20.00
51.81
29.09
146 ± 21.5
150 ± 16.2
162 ± 15.1*,**
63.4
62.0
44.5
36.6
38.0
55.5
Note: *the difference is significant compared to the highly differentiated tu-
mors (p < 0.05).
**The difference is significant compared to moderately differentiated tumors
(p < 0.05)
An analysis of clinical data of BC patients in an as- analysis of clinical data of BC patients in an as-analysis of clinical data of BC patients in an as- of clinical data of BC patients in an as-of clinical data of BC patients in an as- clinical data of BC patients in an as-clinical data of BC patients in an as- data of BC patients in an as-data of BC patients in an as- of BC patients in an as-of BC patients in an as- BC patients in an as-BC patients in an as- patients in an as-in an as- an as-an as- as-as-
pect of molecular phenotype of the tumor has shown
that median age of the patients with luminal А and
В BC su�types was somewhat higher than 55 years�
while the patients with �asal phenotype were signifi- �asal phenotype were signifi- phenotype were signifi-
cantly older �Ta�le 4�.
Table 4. Clinical characteristics of the BC patients with different molecular tu- characteristics of the BC patients with different molecular tu-characteristics of the BC patients with different molecular tu- of the BC patients with different molecular tu-of the BC patients with different molecular tu- the BC patients with different molecular tu-the BC patients with different molecular tu- BC patients with different molecular tu-BC patients with different molecular tu- patients with different molecular tu-patients with different molecular tu- with different molecular tu-with different molecular tu- different molecular tu-different molecular tu- molecular tu-molecular tu- tu-tu-
mor subtypes
Clinical indexes
Molecular subtype of the tumor
Luminal А Luminal В Basal
n % n % n %
Average age, years 59.57 ± 8.7 56.55 ± 5.4 67.16 ± 13.5
Menstrual function:
premenopause
menopause
postmenopause
21
23
36
26.25
28.75
45.00
6
5
7
33.33
27.75
40.92
3
3
29
8.3
8.3
83.3
Stage:
І
ІІ
27
53
33.75
66.25
3
15
16.65
83.25
15
20
42.85
57.41
Histological type:
invasive lobular carcinoma
invasive ductal carcinoma
22
52
27.5
65
4
14
22.2
77.7
15
20
42.85
57.41
Differentiation grade
high
moderate
low
17
43
20
21.25
53
25
3
14
1
16.65
77.7
5.55
13
10
12
37.14
28.57
34.28
The majority of the patients grouped �y receptor
status of the tumor were at postmenopausal period and
with prevalently �asal BC phenotype. A large majority
of the patients with luminal or �asal tumor su�type were
at stage ІІ� luminal B su�type �eing much more frequent.
The percentage of luminal А and luminal В molecular
su�types in invasive ductal carcinoma was respectively
�.� and �.4 times higher than in invasive lo�ular carci-.� and �.4 times higher than in invasive lo�ular carci-� and �.4 times higher than in invasive lo�ular carci- and �.4 times higher than in invasive lo�ular carci-�.4 times higher than in invasive lo�ular carci-.4 times higher than in invasive lo�ular carci-4 times higher than in invasive lo�ular carci-times higher than in invasive lo�ular carci- lo�ular carci-lo�ular carci- carci-carci-
noma. Also� luminal А and luminal В su�types occurred
more frequently in moderately differentiated tumors
compared to those with high or low differentiation grade�
while the percentage of �asal su�type did not differ sig-�asal su�type did not differ sig-su�type did not differ sig- not differ sig-not differ sig- differ sig-differ sig- sig-sig-
nificantly �etween the tumors of different differentiation
grade �see Ta�le 4�.
An analysis of �� expression did not reveal significant
differences in num�er of ��� cells measured �y H-�core
�etween BC of different molecular phenotypes �Ta�le 5�.
We also analy�ed expression of �� in BC with different
molecular phenotype taking into acount the most im- phenotype taking into acount the most im-phenotype taking into acount the most im- taking into acount the most im-taking into acount the most im- most im-most im- im-im-
portant prognostic clinical indexes �menstrual function�
disease stage� histological type and differentiation grade
of a tumor�. It has �een shown that expression of �� in the
luminal А tumors was equally frequent in the patients
Experimental Oncology ��� �������� ���� ��eptem�er���� �������� ���� ��eptem�er� ��eptem�er� ��5
at premenopausal and postmenopausal periods� and
was at average higher than in the patients at menopause.
Expression of �� in the luminal  tumors did not depend
on menstrual function and was significantly higher than
in the luminal А tumors. In the tumors with �asal pheno- the luminal А tumors. In the tumors with �asal pheno-the luminal А tumors. In the tumors with �asal pheno- luminal А tumors. In the tumors with �asal pheno-tumors. In the tumors with �asal pheno-. In the tumors with �asal pheno-In the tumors with �asal pheno- the tumors with �asal pheno-the tumors with �asal pheno- tumors with �asal pheno-tumors with �asal pheno- with �asal pheno-with �asal pheno- �asal pheno-pheno-
type� no expression of �� was registered in the patients
at premenopausal period while in the patients at meno- premenopausal period while in the patients at meno-premenopausal period while in the patients at meno- period while in the patients at meno-period while in the patients at meno- while in the patients at meno-while in the patients at meno- in the patients at meno-in the patients at meno- the patients at meno-the patients at meno- patients at meno-patients at meno- at meno-at meno- meno-meno-
pause or postmenopausal period high expression levels
of �� were o�served which were somewhat lower than
that in luminal  tumors �Ta�le ��.
Table 5. Expression of LF in breast tumors of different molecular subtypes
Molecular
subtype
of the tu-
mor
Number
of tumors Indexes of LF expression in the tumors
n % Number of LF+ cells
(by H-Score)
Number of tumors with
moderate and high
LF expression, %
Luminal А 81 53.0 174.5 ± 18.2 35.7
Luminal В 35 23.5 168.0 ± 13.2 46.4
Basal 35 23.5 175.2 ± 16.7 41.6
Comparison of �� expression in the tumors of different
molecular phenotype �etween the groups with different
disease stage did not reveal the differences �etween the
stages I and II� �ut it has �een noted that at �oth stages
expression of �� in tumors with luminal  and �asal su�- of �� in tumors with luminal  and �asal su�- �� in tumors with luminal  and �asal su�-in tumors with luminal  and �asal su�- tumors with luminal  and �asal su�-s with luminal  and �asal su�- with luminal  and �asal su�-with luminal  and �asal su�- luminal  and �asal su�-and �asal su�- �asal su�- su�-
types was higher compared to su�type A tumors.
In cases of invasive ductal BC� expression of �� was
significantly higher in luminal В tumors than luminal А�
and this index was equal in �asal and luminal A su�types.
In the case of invasive lo�ular carcinoma� expression
of �� was significantly lower in �asal su�type compared
to luminal В su�type� �ut was significantly higher than
in luminal А su�type �see Ta�le ��.
An analysis of �� expression in tumors of different
differentiation grade has shown that in the groups with
moderate and low differentiation grades the highest
expression of �� was present in luminal  su�type com-of �� was present in luminal  su�type com- �� was present in luminal  su�type com-was present in luminal  su�type com- present in luminal  su�type com-present in luminal  su�type com- in luminal  su�type com-in luminal  su�type com- luminal  su�type com-su�type com- com-com-
pared to su�type А. In luminal su�type А tumors of high
differentiation grade the indexes of �� expression were
slightly lower than these in tumors of low and moderated
differentiation grades and equal to these in �asal tumors
�see Ta�le ��.
The correlation analysis did not demonstrate cor-
relation of �� expression with the stage of the disease
�I or II� in all molecular su�types. In invasive ductal carci-I or II� in all molecular su�types. In invasive ductal carci- or II� in all molecular su�types. In invasive ductal carci-or II� in all molecular su�types. In invasive ductal carci- II� in all molecular su�types. In invasive ductal carci-II� in all molecular su�types. In invasive ductal carci-� in all molecular su�types. In invasive ductal carci- in all molecular su�types. In invasive ductal carci- all molecular su�types. In invasive ductal carci-all molecular su�types. In invasive ductal carci- molecular su�types. In invasive ductal carci-molecular su�types. In invasive ductal carci- su�types. In invasive ductal carci-su�types. In invasive ductal carci-
noma �� expression correlated with occurrence of lumi- expression correlated with occurrence of lumi-expression correlated with occurrence of lumi-
nal A su�type while in invasive lo�ular carcinoma expres- while in invasive lo�ular carcinoma expres-while in invasive lo�ular carcinoma expres- lo�ular carcinoma expres-lo�ular carcinoma expres- carcinoma expres-carcinoma expres- expres-expres-
sion of �� showed a positive correlation with occurrence
of luminal В su�type. In the tumors of �oth histological
types with �asal molecular phenotype no correlation was
found �Ta�le 7�. �� expression was in a strong positive
correlation with occurrence of low and moderate dif-
ferentiation grade of luminal B or �asal tumors.
Therefore� the present research has shown that
expression of �� in BC correlated with some important
physiologic and clinical indexes of the disease. The pat-
terns of correlation strongly depended on molecular phe-
notype of this pathology� i.e. luminal A� luminal B or �asal.
Table 7. Correlation between expression of LF in breast tumors of different
molecular subtype and clinical and morphological characteristics
of BC patients
Molecu-
lar subtype
of the tu-
mor
Stage
of the disease
Histological type
of carcinoma Differentiation grade
І ІІ Invasive
ductal
Invasive
lobular High Mode-
rate Low
Luminal А 0.11 0.2 0.43 0.22 0.27 0.18 0.16
Luminal В 0.17 0.23 0.14 0.71 –0.57 0.68 0.23
Basal 0.026 0.14 0.24 0.21 –0.63 0.73 0.06
According to the data of epidemiologic studies� the
development of each particular molecular BC phenotype
could �e affected �y many factors including physiologic�
constitutive and genetic ones [�9]. �or example� high
waist-to-hip ratio is a risk factor for postmenopausal lu-
minal and �asal carcinoma. It is known that �asal BC su�-
type develops more frequently in young Afro-American
women compared to white women. There are some
studies repor ting that �asal carcinoma development could
�e prevented �y weight control and prolonged �reast
feeding [��]. By the data of genetic studies� the majo -
rity of BRCA1-associated tumors are of �asal su�type�
while in the cases with mutated BRCA2 the tumors are
mostly of luminal А and В su�types [��]. In general� the
data of literature evidence that molecular pathogenesis
of BC strongly depends on physiologic and genetic factors
[�4]� and molecular BC su�types represent different forms
of the disease with different etiology and pathogenesis.
Along with this� some recent pu�lications demon-
strate that �iologic heterogeneity of BC could as well
�e affected �y the heterogeneity of expression of mo-
lecular markers that determine BC phenotype� and im-
portant signal pathways involved in the development and
progression of the tumors [��� ��]. In particular� �y the
data of cluster microanalysis� it has �een considered
reasona�le to classify Her�-positive su�type into three
separate su�types �ecause one of them is characteri�ed
�y more unfavora�le prognosis than two others [�4].
Also� one should take into account the existence of two
forms of ER — ER� and ERβ� as far as the latter is dif-
ferently expressed in molecular su�types of BC [�5].
Hyper expression of ERβ is the highest in �asal BC su�-
type and serves as a negative prognostic factor; �y multi-
factor analysis� it is considered to �e an independent risk
factor of BC. It is supposed that screening of BC patients
�y expression of ERβ and ER� may help to assess pro-
liferative activity of the tumors and to make prognostic
indexes more accurate.
Table 6. Expression of LF in breast tumors of different molecular subtypes and clinical and morphological characteristics of BC patients
Molecu-
lar subtype
of the tumor
Menstrual function Stage of the disease
Tumor morphology
Histological type
of carcinoma Differntiation grade
Premeno-
pause Menopause Postmeno-
pause І ІІ Invasive
ductal
Invasive
lobular High Moderate Low
Luminal А 181.3 ± 15.2 160.1 ± 8.0 184.2 ± 17.2 186.3 ± 14.8 180.3 ± 14.4 172.3 ± 21.8 152.4 ± 10.8 183.2 ± 15.3 176.2 ± 17.6 172.4 ± 16.1
Luminal В 235.4 ± 10.2 241.3 ± 16.5 221.5 ± 14.2 216.4 ± 14.0 221.3 ± 12.1 206.1 ± 17.4* 231.2 ± 13.3* 198.2 ± 18.2 223.4 ± 14.2* 229.1 ± 11.7*
Basal − 215.2 ± 18.3 210.7 ± 15.7 198.5 ± 13.7 203.9 ± 18.1 175.1 ± 12.1 182.1 ± 19.6 180.0 ± 15.6 210.0 ± 12.6* 215.6 ± 14.2*
Note:*the difference is significant compared to other molecular subtypes (p < 0.05).
��� Experimental Oncology ��� �������� ���� ��eptem�er�
Taking into account �iological properties of �� and
wide range of its functional activities� we propose to con-
sider �� as an integral �iological index reflecting dif-
ferent changes associated with tumor cell heterogeneity
in a neoplasm� and with individual response of an orga-
nism on particular tumor phenotype. �uch idea is sup-
ported �y the recent data on capa�ility of DNA� different
nucleotides and oligosaccharides to affect the formation
of �� oligomers that differ �y antioxidant and antitumor
activities and �y their interaction with the components
of immune system [��].
The results of the present study on the correlation
�etween the expression of �� in �reast tumors with life
expectancy of BC patients are of special importance.
It seems reasona�le to find the ways of �� correction
in BC patients taking into account the individual patterns
of clinical course of the disease and tumor heterogeneity.
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