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Advances in Brief |
Departments of Biochemistry and Medical Genetics [L. C. M., S. L. R. S., A. P., E. L., H. D.] and Pathology [L. S., S. T., A. A., P. H. W.], University of Manitoba, Faculty of Medicine, Winnipeg, Manitoba R3E OW3, Canada
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ABSTRACT |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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3
signaling pathway is thought to occur and to be a major driving force
in breast tumorigenesis. The assumption derives from the observations
that only a minority of normal human breast epithelial cells have
detectable ER (7–17% ER+ ductal epithelial cells; Ref.
1
), whereas >70% of primary breast cancers are ER+
(2)
. Furthermore, the majority of proliferating cells in
normal human breast tissue is ER-, and estrogen only indirectly
causes proliferation in normal mammary tissues (reviewed in Ref.
3
). However, estrogen can directly cause proliferation of
breast cancer cells (4)
, and many proliferating cells in
ER+ breast tumors are ER+ (5)
.
Factors that enhance and repress receptor activity directly, namely
coactivators and corepressors, now are considered to be important in
mediating steroid receptor transcriptional activity (6)
.
As well, experimental modulation of levels of these two classes of
coregulators was shown to alter steroid receptor transcriptional
activity (7
, 8)
. These data suggest that not only are
ER levels often increased during breast tumorigenesis
(9)
, but it is likely that other factors which modulate
ER activity might also be altered during breast tumorigenesis with
an outcome of enhancement or deregulation of ER signaling that may
underlie alterations of estrogen responsiveness from indirect in normal
breast epithelium to direct in ER+ breast tumor cells. We have
addressed this hypothesis by investigating the expression of two known
coactivators of ER, SRA (7)
and AIB1 (10)
,
and a repressor of ER activity, REA (8)
, at the mRNA
level in ER+ human breast tumors and their matched adjacent normal
breast tissues. The coregulators studied were chosen because they were
identified as either selective for ERs and/or steroid receptors,
e.g., SRA (7)
and REA (8)
, or were
identified previously to be of relevance in human breast cancer
in vivo, e.g., AIB1, which is frequently
amplified in breast tumors in vivo (10)
.
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Materials and Methods |
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In Situ Hybridization.
Paraffin-embedded 5-µm breast tumor and matched adjacent normal
breast tissue sections were analyzed by in situ
hybridization according to a previously described protocol
(12)
. The plasmid pGEM-T-SRAcore, consisting of
pGEM-T-easy plasmid (Promega, Madison, WI) containing a 397-bp
insert of the human SRA cDNA (from nucleotide 300 to 696, numbered
according to GenBank accession no. AF092038), was used as a template to
generate sense and antisense riboprobes. The plasmid pGEM-T-REA,
consisting of pGEM-T-easy plasmid containing a 399-bp insert of the
human REA cDNA (from nucleotide 385 to 783, numbered according to
GenBank accession no. AF150962), was used as a template to generate
sense and antisense riboprobes. UTP 35S-labeled
riboprobes were synthesized using Riboprobe Systems (Promega, Madison,
WI) according to the manufacturer’s instructions. Sense probes were
used as controls. In situ hybridization and washing
conditions were as described previously (12)
. Sections
were developed using Kodak NTB-2 photographic emulsion and
counterstained with Lee’s stain after 2–6 weeks.
RNA Extraction and RT-PCR Conditions.
Total RNA was extracted from 20-µm frozen tissue sections (20
sections/tumor; 35 sections for normal tissues) using Trizol
reagent (Life Technologies, Grand Island, NY)
according to the manufacturer’s instructions and quantified
spectrophotometrically. One µg of total RNA was reverse-transcribed
in a final volume of 25 µl as described previously (13)
.
Primers and PCR Conditions.
The primers used were: (a) SRAcoreU primer
(5'-AGGAACGCGGCTGGAACGA-3'; sense; positions 35–53; GenBank accession
no. AF092038) and SRAcoreL primer (5'- AGTCTGGGGAACCGAGGAT-3';
antisense; positions 696–678; GenBank accession no. AF092038);
(b) AIB1-U primer (5'-ATA CTT GCT GGA TGG TGG ACT-3'; sense;
positions 110–130; GenBank accession no. AF012108) and AIB1-L primer
(5'-TCC TTG CTC TTT TAT TTG ACG-3'; antisense; positions 458–438;
GenBank accession no. AF012108); and (c) REA-U primer
(5'-CGA AAA ATC TCC TCC CCT ACA-3'; sense; positions 385–405; GenBank
accession no. AF150962) and REA-L primer (5'-CCT GCT TTG CTT TTT CTA
CCA-3'; antisense; positions 781–761; GenBank accession no. AF150962).
Radioactive PCR amplifications for SRA were performed and PCR products
were analyzed as described previously (14)
, with minor
modifications. Briefly, 1 µl of RT mixture was amplified in a
final volume of 15 µl in the presence of 1.5 µCi of
[-32P]dCTP (3000 Ci/mmol), 4 ng/µl of each
primer, and 0.3 unit of Taq DNA polymerase (Life
Technologies, Inc.). For SRA, each PCR consisted of 30 cycles (30 s at
60°C, 30 s at 72°C, and 30 s at 94°C). PCR products
were then separated on 6% polyacrylamide gels containing 7
M urea. After electrophoresis, the gels were
dried and exposed for 2 h to a Molecular Imager-FX Imaging screen
(Bio-Rad, Hercules, CA).
PCR amplifications for AIB1 and REA were performed and PCR products were analyzed as described previously (13) , with minor modifications. Briefly, 1 µl of RT mixture was amplified in a final volume of 20 µl, in the presence of 4 ng/µl of each primer and 0.3 unit of Taq DNA polymerase (Life Technologies, Inc.).
For AIB1, each PCR consisted of 30 cycles (30 s at 55°C, 30 s at 72°C, and 30 s at 94°C). For REA, each PCR consisted of 30 cycles (30 s at 57°C, 30 s at 72°C, and 30 s at 94°C). PCR products then were separated on agarose gels stained with ethidium bromide as described previously (13) . Amplification of the ubiquitously expressed GAPDH cDNA was performed in parallel, and PCR products were separated on agarose gels stained with ethidium bromide as described previously (13) . The identity of PCR products was confirmed by subcloning and sequencing, as reported previously (15) .
Quantification of SRA Expression.
Exposed screens were scanned using a Molecular Imager-FX (Bio-Rad) and
the intensity of the signal corresponding to SRA was measured using
Quantity One software (Bio-Rad). Three independent PCRs were performed.
To control for variations between experiments, a value of 100% was
arbitrarily assigned to the SRA signal of one particular tumor measured
in each set of PCR experiments, and all signals were expressed as a
percentage of this signal. In parallel, GAPDH cDNA was
amplified, and after analysis of PCR products on prestained agarose
gels, signals were quantified by scanning using MultiAnalyst (Bio-Rad).
Three independent PCRs were performed. Each GAPDH signal was
also expressed as a percentage of the signal observed in the same tumor
as above. For each sample, the average of the SRA signal was then
expressed as a percentage of the GAPDH signal (arbitrary
units).
Quantification of the Relative Expression of the Deleted SRA
Variant RNA.
It has been shown previously that the coamplification of a wild-type
and a deleted variant SRA cDNA resulted in the amplification of two PCR
products, the relative signal intensity of which provided a reliable
measurement of the relative expression of the deleted variant
(15)
. For each sample, the signal corresponding to the
SRAdel was measured using Quantity One software (Bio-Rad) and expressed
as a percentage of the corresponding core SRA signal. For each case,
three independent assays were performed and the mean determined.
Quantification of REA and AIB1 Expression.
After analysis of PCR products on prestained agarose gels, signals were
quantified by scanning using MultiAnalyst (Bio-Rad). At least, three
independent PCRs were performed. To control for variations between
experiments, a value of 100% was arbitrarily assigned to the REA or
AIB1 signal of one particular sample and all signals were expressed as
a percentage of this signal. For each sample, the average of REA or
AIB1 signals was then expressed as a percentage of the average of the
GAPDH signal (arbitrary units), as described above.
Statistical Analysis.
Differences between normal samples and their matched tumors were tested
using the Wilcoxon matched pairs test, two-tailed. Differences between
the relative expression of cofactors (e.g., logAIB1:REA)
obtained for matched normal and tumor compartments were also tested
using the Wilcoxon matched pairs test, two-tailed. Correlation between
SRA, REA, or AIB1 expression and tumor characteristics was tested by
calculation of the Spearman coefficient R.
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Results |
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shows examples of the results obtained. Antisense RNA probes to SRA
showed a strong signal over the epithelial tumor cells of an ER+ human
breast tumor section (Fig. 1A)
, with little, if any, signal
obtained when sense SRA probes were used on the adjacent section of the
same tumor (Fig. 1C)
. Low levels of SRA expression were
detected mainly over the ductal epithelial cells of normal breast
tissue from the same patient. This result paralleled that for AIB1,
where it was previously shown using in situ hybridization
that AIB1 mRNA expression was significantly increased in breast cancer
cells carrying increased copies of the AIB1 gene compared
with normal breast epithelial cells, although it was not stated that
these samples were from the same patient in this study
(10)
. In contrast, when the in situ expression
of REA mRNA was examined in an ER+ tumor and its matched adjacent
normal breast tissue (Fig. 1, D and E
,
respectively), little difference could be seen between the signal over
the epithelial breast tumor cells compared with the normal breast
epithelial cells. Furthermore, little if any signal was observed when
REA sense probes were used (Fig. 1F)
. These data suggested
that the expression of the steroid receptor-specific coactivator, SRA,
in addition to AIB1 (10)
was significantly increased in
breast tumor cells compared with normal breast epithelial cells,
whereas the expression of a specific ER-repressor was not altered in
breast tumors compared with normal breast epithelial cells. To
investigate this further, we developed a semi-quantitative RT-PCR
approach to measure the expression of these coregulators in multiple
samples of ER+ breast tumors and their matched adjacent normal breast
tissues, as described below.
|
. Therefore, core SRA is expressed in all human breast
tissues, and expression of the deleted SRA is not tumor-specific.
|
). The analysis was confined to
tissues from women whose breast tumor was ER+ as determined by
ligand-binding assays. SRA expression corrected for the
GAPDH signal in each sample for all matched normal and tumor
pairs is shown in Fig. 3A
. The level of core SRA was significantly higher (Wilcoxon
matched pairs test; P = 0.0004) in the tumors
(median = 63 arbitrary units) compared with their
adjacent normal tissue (median = 7 arbitrary units).
When detected, expression of the deleted SRA relative to the core SRA
was not significantly different between normal breast tissue and
tumors (data not shown). These data suggested that core SRA expression
is up-regulated, but the relative expression of a deleted SRA is not
altered, during breast tumorigenesis.
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Altered Expression of AIB1 mRNA between Breast Cancer and Adjacent
Matched Normal Breast Tissues.
To pursue further the possibility that an imbalance in expression of
activators of ER action may occur during breast tumorigenesis, we
investigated in the same samples the expression of another coactivator
of ER activity, AIB1 (10)
. AIB1 is overexpressed in
several human breast tumors (10
, 16)
, although to our
knowledge measurement of its RNA expression in a series of matched
normal and breast tumor tissues was not reported previously.
AIB1-specific primers amplified a predicted 349-bp fragment in normal
breast tissues (Fig. 2B)
, in breast tumors (Fig. 2B)
, and in breast cancer cells (data not shown). Cloning
and sequencing confirmed the identity of the 349-bp PCR product with
AIB1 (10)
. Expression of AIB1 corrected for the
GAPDH signal in each tissue sample for all of the matched
pairs is shown in Fig. 3B
. Expression of AIB1 mRNA was
significantly higher (Wilcoxon matched pairs test;
P = 0.0058) in tumor samples
(median = 67.8 arbitrary units) compared with adjacent
normal tissues (median = 36.6 arbitrary units). These
data are consistent with previous data (10
, 16)
and
suggest that expression of another ER coactivator is significantly
increased during breast tumorigenesis. Expression of AIB1 in this tumor
cohort was not correlated with PR status, grade, tumor size, or nodal
status.
Detection of REA mRNA in Normal and Neoplastic Human Breast
Tissues.
To determine whether alterations in expression of a corepressor,
i.e., REA, also occurred during breast tumorigenesis, an
RT-PCR approach was developed. The REA-specific primers amplified a
predicted 397-bp fragment in normal breast tissues (Fig. 2C)
, in breast tumors (Fig. 2C)
, and in breast
cancer cells (data not shown). Cloning and sequencing confirmed the
identity of the 397-bp PCR product as REA (8)
. This
product was used to probe Northern blots of RNA extracted from human
breast cancer cells and breast tumor biopsies. An 
1.5 kb transcript
was detected, consistent with the REA mRNA described previously (data
not shown; Ref. 8
).
To determine whether REA expression was potentially altered during
breast tumorigenesis, REA mRNA levels were measured in ER+ breast
tumors and their adjacent normal breast tissues (examples in Fig. 2C
) from the same 19 different patients described above. REA
expression corrected for the GAPDH signal (Fig. 2D)
in each sample for all matched pairs is shown in Fig. 3C
. REA expression was not significantly different (Wilcoxon
matched pairs test; P = 0.110) in the tumors
(median = 84.6 arbitrary units) compared with the
adjacent normal tissues (median = 69.8 arbitrary units).
REA expression in the tumors was not correlated with PR status, grade,
tumor size, or nodal status.
Altered Relative Expression of Coactivators and Repressors during
Human Breast Tumorigenesis.
The above data suggest that alterations in the relative expression of
ER activators and repressor occurred during breast tumorigenesis. To
address this question, the relative expression of SRA and AIB1 mRNA to
REA mRNA was compared between the breast tumors and the normal tissues.
Results are shown in Fig. 4
. The ratio of SRA:REA (Fig. 4A)
was significantly higher
(Wilcoxon matched pairs test; P = 0.0003) in
tumors (median = 87 arbitrary units) compared with
normal tissues (median = 12 arbitrary units). Similarly,
the ratio of AIB1:REA (Fig. 4B)
was significantly higher
(Wilcoxon matched pairs test; P = 0.0414) in
tumors (median = 86.7 arbitrary units) compared with
normal tissues (median = 61.3 arbitrary units).
Furthermore, the ratio of SRA:AIB1 (Fig. 4C)
was
significantly higher (Wilcoxon matched pairs test;
P = 0.0058) in tumors (median = 94.3 arbitrary units) compared with normal tissues
(median = 22.8 arbitrary units), suggesting that the
relative expression of ER coactivators may also change during breast
tumorigenesis.
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Discussion |
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SRA and AIB1 likely mediate their effects on ER activity via different mechanisms (7) . SRA, unlike AIB1, functions as an RNA molecule (7) . Also SRA requires the structurally and functionally distinct N-terminal/AF1 region of steroid receptors compared with AIB1, which requires the COOH-terminal/AF2 domain (6) , possibly suggesting that estrogen target gene cascades could be differentially regulated by the relative expression of different coactivators. Therefore ER signaling could be altered during breast tumorigenesis. Such alterations during breast tumorigenesis are supported by the marked difference in breast epithelial growth responses to estrogen occurring during this process, i.e., from indirect in normal to direct in breast cancer cells (3, 4, 5) .
It is the core region of SRA that is necessary and sufficient for the coactivator activity of SRA (7) . Our primers for SRA (14) will detect all SRA isoforms containing core sequences, and we assume that our measurement of all intact core SRA-like RNAs correlates with total SRA activity present in any one tissue. These primers also detect a previously described isoform of SRA (GenBank accession no. AA426601) containing a deletion of sequences within the SRA core. Deletions within the core were reported previously to result in the loss of SRA activator function (7) . It is likely that this deleted variant is inactive with respect to coactivator activity and could function to alter steroid signaling in breast tumors and contribute to the more aggressive phenotype associated with poorer-prognosis tumors, which include characteristics such as high grade and large tumor size. A similar relationship of the relative expression of the deleted SRA and grade was also found in a previously described but separate breast tumor cohort (14) .
Recently, REA was identified as a specific repressor of ligand-occupied
ER (ER and ERß, but not other steroid or nuclear receptors)
transcriptional activity (8)
. Furthermore, part of its
mechanism appeared to involve competition with coactivators such as
SRC-1 (6)
. It differed from previously identified
corepressors such as N-CoR/SMRT (6)
because it was
selective for ER as opposed to generally effecting members of the
nuclear receptor family (8)
. Because REA was selective for
ER, it was relevant to investigate it in breast tissues. Our data
suggest that REA expression is not altered in breast tumors compared
with normal breast tissues.
Although the assessment of expression by RT-PCR will only allow measurement of global expression of these genes in heterogeneous tissue sections, our in situ hybridization data support the conclusion that the major cell type expressing SRA or REA in breast tissue is the epithelial cell, either normal or neoplastic. Previous data have confirmed that AIB1 mRNA is expressed in the epithelial component of both normal and neoplastic breast tissue (10) . Therefore, our RT-PCR results likely represent expression differences in the epithelial components of the tissues examined. Furthermore, SRA, AIB1, and REA were shown to be expressed in human breast cancer cell lines in culture (7 , 8 , 10) . Our in situ hybridization data are consistent with the RT-PCR data as well. Although further study is needed to confirm the relation between ER and these cofactors within individual cells, the data support the hypothesis that relative changes between coactivators (SRA and AIB1) and a corepressor (REA) can occur in breast tumorigenesis in vivo, an important point required to provide in vivo relevance for several previously published studies concerning altered coactivators and coregulators using laboratory model systems. Parallel in situ studies of AIB1 and REA protein levels, but not SRA (active as an RNA molecule), are required to provide unequivocal evidence of the relative changes between coactivators and corepressors during breast tumorigenesis. Unfortunately, there are presently no commercially available antibodies to REA, and available AIB1 antibodies cannot be used for immunohistochemical analysis. However, the available data based on Western blot analysis of breast and ovarian cancer cell line extracts suggest that there is a quantitative relationship between AIB1 mRNA and protein levels (17 , 18) .
Recently, a study was published (19)
in which both ER
and the coactivator TIF2 were found to be significantly increased in
intraductal carcinomas compared with normal mammary gland tissue. This
study suggested as well that ER and a general corepressor N-CoR are
reduced in invasive breast cancer compared with DCIS. Although these
results are consistent with our data and support the hypothesis that
there may be an up-regulation of factors associated with increased ER
signaling in breast tumorigenesis, the number of cases screened was
small compared with our study, the normal samples and DCIS samples were
not matched, i.e., were not from the same patient, to the
invasive breast cancer samples, and furthermore not all tumors were
ER+. These factors introduce biological heterogeneity because the
natural history of ER+ and ER- breast cancers is distinct, and it is
likely that the factors involved in the development of ER-
versus ER+ breast cancer are different. Also, the lack of
matched samples with respect to comparisons among normal, intraductal,
and invasive breast cancer introduces significant issues associated
with patient-to-patient variability with respect to alterations which
may be influenced by age and menopausal and other hormonal status, and
may be significantly different between the groups compared and
therefore confound the interpretation of the results.
We have used matched normal and breast cancer tissues as surrogates for breast tumorigenesis; however, it is acknowledged that breast tumorigenesis is a complex process, and an investigation of different morphological lesions thought to parallel the evolution of normal breast tissue to invasive breast cancer is necessary before more definite conclusions can be made. However, this study is the first, to our knowledge, that uses multiple matched samples of normal breast tissue and their ER+ tumors, and provides evidence that the relative expression of coactivators and corepressors, which are highly relevant with respect to the ER signal transduction pathway, can be significantly altered between normal human breast and breast tumors in vivo.
In conclusion, although our study is small, the results presented are
consistent with the hypothesis that a significant up-regulation of ER
signaling occurs during breast tumorigenesis in ER+ tumors. This is
reflected not only in the increased expression of ER shown
previously, but now also in an increase in factors that can activate ER
activity without a concomitant increase in factors that can repress ER
activity. Despite the obvious need to study protein levels where
appropriate, when reagents become available, the possibility now exists
that an imbalance in the expression of repressors and activators of
ER can occur during human breast tumorigenesis in vivo
and may contribute to altered estrogen action, which is known to occur
during this process.
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FOOTNOTES |
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1 Supported by grants from the Canadian Breast
Cancer Research Initiative and the United States Army Medical Research
and Materiel Command. The Manitoba Breast Tumor Bank is supported by
funding from the National Cancer Institute of Canada. P. H. W. and
L. C. M. are Medical Research Council of Canada Scientists. 
2 To whom requests for reprints should be
addressed, at Department of Biochemistry and Medical Genetics,
University of Manitoba, Winnipeg, MB, R3E OW3, Canada. Phone:
(204) 789-3233; Fax: (204) 789-3900; E-mail: lcmurph{at}cc.umanitoba.ca
3 The abbreviations used are: SRA, steroid
receptor RNA activator; AIB1, amplified in breast cancer-1; REA,
repressor of estrogen receptor activity; ER, estrogen receptor; PR,
progesterone receptor; RT, reverse transcription; GAPDH,
glyceraldehyde-3-phosphate dehydrogenase; DCIS, intraductal
carcinoma.
Received 1/ 6/00. Accepted 10/ 3/00.
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and ß mRNA expression during human breast tumorigenesis. Cancer Res., 58: 3197-3201, 1998., estrogen receptor-ß, coactivators and corepressors in breast cancer. Clin. Cancer Res., 6: 512-518, 2000.This article has been cited by other articles:
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V. Y. Lin, E. M. Resnick, and M. A. Shupnik Truncated Estrogen Receptor Product-1 Stimulates Estrogen Receptor {alpha} Transcriptional Activity by Titration of Repressor Proteins J. Biol. Chem., October 3, 2003; 278(40): 38125 - 38131. [Abstract] [Full Text] [PDF]
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L.-A. Martin, I. Farmer, S. R. D. Johnston, S. Ali, C. Marshall, and M. Dowsett Enhanced Estrogen Receptor (ER) {alpha}, ERBB2, and MAPK Signal Transduction Pathways Operate during the Adaptation of MCF-7 Cells to Long Term Estrogen Deprivation J. Biol. Chem., August 15, 2003; 278(33): 30458 - 30468. [Abstract] [Full Text] [PDF]
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J. Matthews and J.-A. Gustafsson Estrogen Signaling: A Subtle Balance Between ER{alpha} and ER{beta} Mol. Interv., August 1, 2003; 3(5): 281 - 292. [Abstract] [Full Text] [PDF]
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C. K. Osborne, V. Bardou, T. A. Hopp, G. C. Chamness, S. G. Hilsenbeck, S. A. W. Fuqua, J. Wong, D. C. Allred, G. M. Clark, and R. Schiff Role of the Estrogen Receptor Coactivator AIB1 (SRC-3) and HER-2/neu in Tamoxifen Resistance in Breast Cancer J Natl Cancer Inst, March 5, 2003; 95(5): 353 - 361. [Abstract] [Full Text] [PDF]
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R. Schiff, S. Massarweh, J. Shou, and C. K. Osborne Breast Cancer Endocrine Resistance: How Growth Factor Signaling and Estrogen Receptor Coregulators Modulate Response Clin. Cancer Res., January 1, 2003; 9(1): 447S - 454S. [Abstract] [Full Text] [PDF]
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C. W. Gregory, E. M. Wilson, K. B. C. Apparao, R. A. Lininger, W. R. Meyer, A. Kowalik, M. A. Fritz, and B. A. Lessey Steroid Receptor Coactivator Expression throughout the Menstrual Cycle in Normal and Abnormal Endometrium J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2960 - 2966. [Abstract] [Full Text] [PDF]
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and the tumor samples by 
. Each
matched normal and tumor sample is joined by a line.
Arrows, the median value in each group.
A, the level of SRA expression in normal tissue is
significantly different to the level of SRA expression in the tumor
tissues (Wilcoxon matched pairs test, two-tailed;
P = 0.0004). B, the level
of AIB1 expression in normal tissue is significantly different
from that in the tumor tissues (Wilcoxon matched pairs test,
two-tailed; P = 0.0058).
C, the level of REA expression in normal tissue is not
significantly different from the level of REA expression in the tumor
tissues (Wilcoxon matched pairs test, two-tailed;
P = 0.110).