Down-regulation of ABCC11 protein (MRP8) in human breast cancer
Aim of this article is to investigate the expression of ABCC11 (MRP8) protein in normal breast tissue, and examine the difference in ABCC11 mRNA and protein expression between normal breast and breast cancer tissues taking into account ABCC11 genotype (a functional SNP, rs17822931) and estrogen rece...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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nasplib_isofts_kiev_ua-123456789-323172025-02-10T00:14:39Z Down-regulation of ABCC11 protein (MRP8) in human breast cancer Sosonkina, N. Nakashima, M. Ohta, T. Niikawa, N. Starenki, D. Original contributions Aim of this article is to investigate the expression of ABCC11 (MRP8) protein in normal breast tissue, and examine the difference in ABCC11 mRNA and protein expression between normal breast and breast cancer tissues taking into account ABCC11 genotype (a functional SNP, rs17822931) and estrogen receptor (ER) status. We are grateful to Dr. Vladimir Saenko, Nagasaki University, for his valuable and critical comments. This study was supported by Grant-in-Aid for Science Research (Category B) for N. Niikawa from the Ministry of Education, Culture, Sports, Science and technology of Japan and Research fund in Health Sciences University of Hokkaido. 2011 Article Down-regulation of ABCC11 protein (MRP8) in human breast cancer / N. Sosonkina, M. Nakashima, T. Ohta, N. Niikawa, D. Starenki // Experimental Oncology. — 2011. — Т. 33, № 1. — С. 42–46. — Біліогр.: 22 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/32317 en Experimental Oncology application/pdf Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Original contributions Original contributions |
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Original contributions Original contributions Sosonkina, N. Nakashima, M. Ohta, T. Niikawa, N. Starenki, D. Down-regulation of ABCC11 protein (MRP8) in human breast cancer Experimental Oncology |
| description |
Aim of this article is to investigate the expression of ABCC11 (MRP8) protein in normal breast tissue, and examine the difference in ABCC11 mRNA and protein expression between normal breast and breast cancer tissues taking into account ABCC11 genotype (a functional SNP, rs17822931) and estrogen receptor (ER) status. |
| format |
Article |
| author |
Sosonkina, N. Nakashima, M. Ohta, T. Niikawa, N. Starenki, D. |
| author_facet |
Sosonkina, N. Nakashima, M. Ohta, T. Niikawa, N. Starenki, D. |
| author_sort |
Sosonkina, N. |
| title |
Down-regulation of ABCC11 protein (MRP8) in human breast cancer |
| title_short |
Down-regulation of ABCC11 protein (MRP8) in human breast cancer |
| title_full |
Down-regulation of ABCC11 protein (MRP8) in human breast cancer |
| title_fullStr |
Down-regulation of ABCC11 protein (MRP8) in human breast cancer |
| title_full_unstemmed |
Down-regulation of ABCC11 protein (MRP8) in human breast cancer |
| title_sort |
down-regulation of abcc11 protein (mrp8) in human breast cancer |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2011 |
| topic_facet |
Original contributions |
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https://nasplib.isofts.kiev.ua/handle/123456789/32317 |
| citation_txt |
Down-regulation of ABCC11 protein (MRP8) in human breast cancer / N. Sosonkina, M. Nakashima, T. Ohta, N. Niikawa, D. Starenki // Experimental Oncology. — 2011. — Т. 33, № 1. — С. 42–46. — Біліогр.: 22 назв. — англ. |
| series |
Experimental Oncology |
| work_keys_str_mv |
AT sosonkinan downregulationofabcc11proteinmrp8inhumanbreastcancer AT nakashimam downregulationofabcc11proteinmrp8inhumanbreastcancer AT ohtat downregulationofabcc11proteinmrp8inhumanbreastcancer AT niikawan downregulationofabcc11proteinmrp8inhumanbreastcancer AT starenkid downregulationofabcc11proteinmrp8inhumanbreastcancer |
| first_indexed |
2025-12-02T02:43:11Z |
| last_indexed |
2025-12-02T02:43:11Z |
| _version_ |
1850362709441249280 |
| fulltext |
42 Experimental Oncology 33, 42–46, 2011 (March)
DOWN-REGULATION OF ABCC11 PROTEIN (MRP8) IN HUMAN
BREAST CANCER
N. Sosonkina1, M. Nakashima2, T. Ohta1, N. Niikawa1, D. Starenki1*
1Research Institute of Personalized Health Science, Health Sciences University of Hokkaido, Tobetsu,
Hokkaido 061-0293, Japan
2Departments of Molecular Pathology, Nagasaki University Graduate School of Biomedical Science,
Nagasaki 852-8523, Japan
Aim: To investigate the expression of ABCC11 (MRP8) protein in normal breast tissue, and examine the difference in ABCC11 mRNA
and protein expression between normal breast and breast cancer tissues taking into account ABCC11 genotype (a functional SNP,
rs17822931) and estrogen receptor (ER) status. Methods: Sections of paraffin-embedded normal and malignant tissues from
10 patients with invasive ductal carcinoma were used for immunohistochemical analysis. DNA and RNA were extracted from the
same sections and used for genotyping and ABCC11 transcript expression measurement by quantitative RT-PCR. Results: A strong
expression of ABCC11 was found in epithelial and myoepithelial cells of normal breast lobules and ducts in individuals with different
ABCC11 genotypes. A predominant decrease of ABCC11 expression was observed in malignant tissue compared to normal beast
specimen (8 of 10 cases), despite four out of ten tumors showed the elevated ABCC11 mRNA level as compared to the normal coun-
terpart. Neither ABCC11 mRNA nor protein expression in normal or cancerous tissue correlated with ER status. Conclusion: The
expression of ABCC11 protein appears to be decreased in most BC. The effect of ABCC11 protein on breast cancer chemosensitivity
is likely to be more complex than that which can be directly inferred from ABCC11 genotype and mRNA expression level in the tumor.
Key Words: ABCC11 mRNA expression, MRP8 expression, normal breast, breast cancer.
Human ATP-binding cassette (ABC) transport
proteins have an essential function of extruding toxins
from cells [1]. Namely this function brings ABC trans-
porters into the focus of the studies of multidrug re-
sistance of tumor cells. Starting with the ABCB1 gene
product, MDR1, several other transporters have been
shown to cause anti-cancer drug resistance in cell
culture through an increased efflux and decreased
intracellular accumulation of chemotherapeutic agent
[2]. Most ABC transporters associated with tumor
resistance belong to the ABCC subfamily.
The ABCC11 gene product (also known as MRP8)
is one of nine multidrug resistances (MDR)-associated
proteins of the ABCC subfamily. ABCC11 substrates
include cyclic nucleotides, monoanionic bile acids,
steroid sulfates, estradiol 17-β-D-glucuronide [3–4].
ABCC11 has been proved to confer resistance to che-
motherapeutic drugs 5-fluorouracil (5-FU) [5] and
pemetrexed (MTA, Alimta) [6].
Profiling of MDR proteins expression in cancer
cells is an important direction in exploring of drug
resistance mechanisms and discovering biomarkers
of a particular tumor type. Breast cancer (BC), as the
most common type of non-skin cancer in women and
the fifth most common cause of cancer death, involves
an intense research effort in this regard. Apart from
MDR1 [7], no evidence has been reported yet on the
relationship of ABC transporters with drug resistance
of BC cells. At the same time, MDR genes transcripts,
including ABCC11 mRNA, have been shown to be over-
expressed in BC [8–9]. Elevated expression levels
of ABCC11 in estrogen receptor (ER)α-positive, as com-
pared to ERα-negative BC, were reported by Honorat
et al. [10]. The authors also observed the regulation
of the ABCC11expression by estrogen in MCF7 breast
cancer cell line [10]. However, no studies addressing
differential ABCC11 expression in normal and cancerous
breast tissues have been done so far. Similarly, nothing
currently is known about the ABCC11 protein expres-
sion in normal breast tissue in comparison to the tumor.
This work was set out to examine the ABCC11 tran-
script and ABCC11 protein expression in BC and
matched normal breast specimens in 10 women in rela-
tion with ER status. We also analyzed ABCC11 expres-
sion levels with regard to a functional SNP (rs17822931)
in the ABCC11 gene that apparently affects the trans-
port activity of the protein [11–14].
MATERIALS AND METHODS
Samples. The study protocol was approved by the
Committee for the Ethical Issues of Human Genome
and Gene Analysis of Health Sciences University of Hok-
kaido. A total of 10 BC and normal mammary gland
specimens which were located away from the tumor
of the same patient were selected from pathological
archives of the Department of Molecular Pathology,
Atomic Bomb Disease Institute, Nagasaki University,
Japan. Clinicopathological information on BC samples
including ER status (positive/negative, as a part of rou-
tine pathological diagnosis of BC) was obtained from
patients’ records. Serial 5 �m sections of normal tissue
and BC surgical specimen mounted on microscope
slides were available for the study. Sections of all speci-
Received: February 14, 2011.
*Correspondence: Fax: 0133-23-1782;
E-mail: starenki@hoku-iryo-u.ac.jp
Abbreviations used: BC — breast cancer; ER — estrogen receptor;
FFPE — formalin-fixed paraffin-embedded; MPR — multidrug resis-
tance protein; SNP — single nucleotide polymorphism.
Exp Oncol 2011
33, 1, 42–46
43 Experimental Oncology 33, 42–46, 2011 (March)
mens were stained with hematoxylin and eosin and re-
analyzed by an experienced pathologist to confirm that
each BC specimen contained cancerous tissue, and
each normal breast sample was free of malignant tissue.
DNA extraction and genotyping. DNA was ex-
tracted from paraffin-embedded sections with DEXPAT
reagent (TaKaRa Bio Inc., Otsu, Japan) according
to the manufacturer’s protocol. DNA was further pre-
cipitated with ethanol, reconstituted in TE buffer and
2 μl was used as a template in genotyping reactions.
The samples were genotyped by TaqManTM assay using
the reagents, primers and probes (Applied Biosystems
by Life Technologies, Foster City, CA, USA) and thermal
cycling conditions described in our recent work [15].
The assays were run in a Rotor-Gene Q (QIAGEN,
Tokyo, Japan). Four replicates of each sample were
analyzed. Genotypes were assessed by automated
allelic discrimination analysis and by comparison with
external controls with known genotypes.
Quantitative real-time (qRT)-PCR. RNA was
extracted from FFPE sections mounted on micro-
scope slides with RNeasy FFPE kit (QIAGEN, Tokyo,
Japan) according to the manufacturer’s protocol with
additional 3 min incubations at 50 ºC after adding
of 1 ml of xylene, and before the first centrifugation
step. cDNA was then synthesized using SuperScript
First-Strand Synthesis System for RT-PCR (Invitrogen,
Carlsbad, CA, USA). Three independent reverse-
transcription reactions were done for each sample,
and the content of each of the three tubes was used
as an individual template in triplicate qRT-PCR. Com-
mercially available TaqMan® Gene Expression Assays
(Applied Biosystems by Life Technologies, Foster City,
CA, USA) were used to analyze the target (ABCC11 and
ESR1) and reference cDNAs (MRLP19, TBP, TFRC).
The respective assay IDs are listed in Table.
Table. Gene Expression Assays used as primers for quantitative RT-PCR
Gene symbol Assay ID
ABCC11 Hs01090769_m1
ESR1 Hs00174860_m1
MRLP19 Hs00608522_m1
TBP Hs00427621_m1
TFRC Hs00951083_m1
Note: Assays were purchased from Applied Biosystems by Life Technolo-
gies (Foster City, CA, USA).
MRLP19, TBP and TFRC were selected as refer-
ence genes for normalization according to Drury et al.
[16], who found these to be particularly suitable for
gene expression analysis in FFPE material. To meet
another important condition for qRT-PCR of FFPE
samples [17], expression assays for all genes were
selected to amplify the target as close to the 3’ end
as possible. To comply with the MIQE Guidelines [18],
each set of primers was tested for efficacy using se-
rial dilutions of a control cDNA sample. Reaction was
performed in TaqMan® Universal PCR Master Mix
(Applied Biosystems by Life Technologies, Foster City,
CA, USA) under the following thermal profile: after the
initial incubation at 50 ºC for 2 min followed by 95 ºC for
10 min, reaction was cycled 55 times at 95 ºC for 15 sec
and at 60 ºC for 1 min in a Rotor-Gene Q machine. Geo-
metrical mean of the relative concentrations of ABC-
C11and ESR1 against each of MRLP19, TBP, and TFRC
was used as the expression index in further analysis.
Antibodies. The ERα was detected in human
breast tissues with a mouse monoclonal antibody
NCL-ER-6F11 (Novocastra Laboratories, Newcastle,
UK) diluted 1:80. ABCC11 was detected with rabbit
polyclonal antibody provided by Dr. K.Yoshiura at the
dilution of 1:100. For the immunofluorescent detection
of the proteins, we used secondary anti-mouse –Alexa
Fluor 594 and anti-rabbit –Alexa Fluor 488 (Invitrogen,
Carlsbad, CA, USA) conjugates at 1:200 dilution. All
antibodies were diluted in 1% BSA (Sigma, St Louis,
MO, USA) in 0.01M PBS.
Immunohistochemical double labeling for
ER and ABCC11. Sections of paraffin-embedded tis-
sues were mounted on aminoalkylsilane-coated slides,
deparaffinized, and rehydrated. The sections were se-
quentially incubated in four changes of boiling 0.01 M ci-
trate buffer, pH 6.0, 5 min each, 2% hydrogen peroxide
at room temperature for 15 min, three changes of PBS,
5 min each, and in 5% BSA blocking solution at room
temperature for 20 min. Then the slides were washed
in PBS for 10 min and incubated overnight at 4 °C in the
mixture of primary anti-ER and anti-ABCC11 antibodies
diluted as described above. After incubation the sec-
tions were washed in three changes of PBS, 10 min
each, followed by 30 min incubation at room tempera-
ture with the mixture of the secondary antibodies. The
slides were then rinsed in four changes of PBS, covered
with Vectashield H-1200/DAPI mounting media (Vector
Laboratories, Burlingame, CA, USA) and analyzed under
a Biorevo BZ-9000 (Keyence Corp., Woodcliff Lake, NJ,
USA) fluorescent microscope. The three-color images
were acquired, merged and processed to remove haze
and adjust the background using the built-in software.
Green fluorescence intensity (ABCC11) was measured
in the images and normalized to blue fluorescence in-
tensity (nuclei) using Image-Pro software (v.4.5, Media
Cybernetics, Bethesda, MD, USA).
RESULTS
Localization of ABCC11 in normal breast tis-
sue. The localization of the ABCC11 protein product
in normal breast lobules and terminal ducts was
determined by immunochistochemistry. The high
level of ABCC11 expression was seen in all 10 speci-
mens (Fig. 1, 1N-10N). As shown in Fig. 1-3N, the
ABCC11 protein was detected within the layer of both
luminal epithelial (Fig.1-3N, hollow arrow) and basal
myoepithelial cells (Fig. 1-3N, solid arrow). Of note,
normal mammary cells appear to express ABCC11 re-
gardless of the rs178829931 genotype or ER status.
Expression of ABCC11 mRNA. We compared
ABCC11 transcript levels in normal breast tissues and
in tumors. As shown in Fig. 2, the increased ABCC11 ex-
pression in cancerous tissue was seen in 4 of 10 pa-
tients (Patients 1, 6, 7, and 10). In six patients, the
decreased expression as compared to normal breast
was observed. The changes in ABCC11 expression
44 Experimental Oncology 33, 42–46, 2011 (March)
were irrelevant to the tumor ER status (the obtained
ER staining results perfectly corresponded to those
in patients’ medical records in all cases) or 538G > A
(rs178829931) polymorphism. Moreover, no correla-
tion was found between ABCC11 and ESR1 expression
in tumors (Pearson’s correlation coefficient, r = 0.175)
or in normal breast tissue (r = -0.182).
Expression of ABCC11 in BC. IHC analysis revealed
an evident decrease in ABCC11 expression in tumor tis-
sues in 8 patients as compared to the normal counterpart
(Fig. 1, 1C–5C, 7C, 9C, and 10C). The quantification
of green fluorescence intensity revealed 1.8- to 6.7-fold
decrease of the signal (Fig. 3). ABCC11 levels in the
remaining two BC samples were comparable to those
in normal tissue (Fig. 1, 6C, 8C), 1.17- to 1.39-fold sig-
nal fading (see Fig. 3). Thus, none of examined tumor
samples showed ABCC11 over-expression as compared
to normal breast. Interestingly, in three BC samples a very
low protein expression was detected despite the high
mRNA levels (Fig. 1, 1C, 9C, and 10C).
DISCUSSION
In the present study we found a predominant
decrease of the ABCC11 product, ABCC11 protein,
expression in BC as compared to the normal breast
tissue of the same patient, and such decrease did not
correlate with ABCC11 mRNA level. Only two of ten
BC specimens displayed ABCC11 expression similar
to that in the normal tissue.
The function of ABCC-subfamily transporters and
their role in tumor resistance are intensively investigat-
ed. ABCC11 mRNA expression data are also available
from rather numerous BC analyses. Several studies
reported ABCC11 mRNA over-expression in BC tissue
and BC cell lines [8–9, 19–20]. Park et al. [19] observed
the increased expression of ABCC11 in BC patients
with residual disease compared to those who achieved
a complete response, although the authors did not
include ABCC11 in their optimal molecular prognosti-
cator of BC response to neoadjuvant chemotherapy.
Honorat et al. [10] pointed at the possibility of estrogen
involvement in the regulation of ABCC11 expression.
On the other hand, estrogen-responsive genes have
been implicated in acquired resistance to tamoxifen
or aromatase inhibitors [21]. Taken together, the
existing knowledge on ABCC11 expression in BC indi-
cates that this protein may play a role in the regulation
of chemotherapy response.
Most studies of tumor resistance are performed
using cell cultures. However, the origin of cells used
to establish cell lines does not represent all tumor types
and the conditions of cell culturing appear to limit trans-
lational application of the results obtained in cell lines.
Our results show that in a real tissue, ABCC11 mRNA
level poorly correlates with protein expression. This find-
ing emphasizes the importance of parallel examination
of ABCC11 mRNA and protein product in normal and
malignant breast tissue. As we demonstrated, surgical
samples stored as FFPE tissues could be successfully
used for such an analysis.
AA
GA
AA
GA
AA
GA
AA
GG
AA
AA
1
2
3
4
5
6
7
8
9
10
N С
Fig. 1. Expression of ABCC11 and ERα in normal mammary (N,
left column) and breast cancer (C, right column) tissues of 10 pa-
tients. The ABCC11 protein (green) and the ESR1 protein (red)
were detected on 5 μm FFPE sections and merged as described
in Materials and Methods. The DAPI counterstaining of the nuclei
appears in blue. The genotype at rs17822931 of each patient
is indicated on the right of each normal-cancer image pair
45 Experimental Oncology 33, 42–46, 2011 (March)
1 2 3 4 5 6 7 8 9 10
0,0
0,5
1,0
1,5
2,0
2,5
ABCC11
ESR1
Fo
ld
c
ha
ng
e
of
m
RN
A
ex
pr
es
si
on
(c
an
ce
r/n
or
m
)
Patient
Fig. 2. Expression of ABCC11 and ESR1 transcripts in normal
mammary tissue and breast cancer tissue of 10 patients. Expres-
sion was measured by qRT-PCR, and the geometrical mean
of ABCC11 and ESR1 relative concentrations against three refer-
ence genes was used as an estimate of gene expression level.
Black diamonds represent the ratio of ABCC11 mRNA expression
level in BC to that in normal tissue. Circles represent the changes
in ESR1 mRNA expression
0,0
0,5
1,0
1,5
2,0
2,5
ER +
C
Re
la
tiv
e
AB
CC
11
le
ve
l
AA
GA, GG
N CN
ER -
Fig. 3. Down-regulation of ABCC11 protein in BC tissues. The
relative intensity of green signal was determined in normal and
malignant tissue images as described in Materials and Methods.
The decrease of ABCC11 fluorescence intensity from normal (N)
to cancer (C) tissue was observed in each patient irrespectively
of ER status or genotype
To better understand the role of ABCC11 in BC, the
knowledge of protein localization in normal mammary
gland is essential. Our experiments employing immuno-
histochemical staining demonstrated that ABCC11 is ex-
pressed in epithelial and myoepithelial cells of breast lob-
ules and ducts. The presence of ABCC11 in epithelial cells
of normal terminal duct lobular unit (TDLU), the structural
and functional unit of the breast, implies the involvement
of this transporter in secretion function of the mammary
gland, and is consistent with the finding that the volume
of colostrum secretion depends on ABCC11 genotype
at rs17822931 [12]. Of interest is the observation that
ABCC11 is expressed also in myoepithelial cells which
do not express ERα [22]. Our examination of ABCC11 lo-
calization may suggest that the protein participates not
only in apocrine secretion, but also in metabolite trans-
port into the stroma embedding ducts and lobules.
Transport activity of ABCC11 is strongly affected
by a SNP at nucleotide 538 (538G > A, rs17822931)
of ABCC11 [14]. This SNP determines human earwax
type, and associates with some functions of apocrine
glands. Individuals with the AA genotype are character-
ized by the reduced cerumenous secretion [14] and
a nearly complete loss of axillary odor [11] as compared
to those homozygous or heterozygous for wild-type
G allele. However, as the results reported here reveal,
the ABCC11 polymorphism does not seem to influence
the localization of the ABCC11 protein in the mammary
gland. The ABCC11 expression pattern was similar in the
mammary glands of different ABCC11 genotype carriers,
suggesting that non-functional ABCC11 is not degraded
but incorporated into the cellular membrane. Similar
observations were previously made in the sweat glands
[11]. Although ABCC11 expression in normal breast
or BC is independent of rs17822931, functional studies
of the ABCC11 SNP are potentially useful. This could be il-
lustrated by the study of the ABCC11 role in lung cancer
cell resistance to MTA, in which ABCC11 expression level
did not correlate with IC50 for MTA; yet ABCC11 genotype
affected chemosensitivity [6].
In conclusion, the expression of ABCC11 protein which
localizes in epithelial and myoepithelial cells of normal
breast lobules and ducts is likely to be decreased in the
majority of BC or it may be comparable to that in normal
tissue in some cases. It remains to be elucidated whether
ABCC11 loss or retention in BC is functionally relevant
to tumor development or may affect clinical course and
prognosis. Therefore, further studies of ABCC11 expres-
sion in BC are warranted to determine its usefulness for
decision making on BC therapy protocol.
ACKNOWLEDGEMENTS
We are grateful to Dr. Vladimir Saenko, Nagasaki Uni-
versity, for his valuable and critical comments. This study
was supported by Grant-in-Aid for Science Research
(Category B) for N. Niikawa from the Ministry of Education,
Culture, Sports, Science and technology of Japan and
Research fund in Health Sciences University of Hokkaido.
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