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Laboratoire d’Oncologie Moléculaire Humaine, Centre Oscar Lambret, 59020 Lille Cédex, France
ABSTRACT
We
measured the expression of the type I growth factor receptor gene
family [epidermal growth factor receptor (EGFR), c-erbB-2, c-erbB-3
and c-erbB-4] in a series of 365 unselected primary breast cancers.
The expression was quantified with a real-time one-step reverse
transcriptase-PCR (RT-PCR) assay, based upon the 5' nuclease activity
of the Taq polymerase and using an Abi Prism 7700 Sequence Detector
System (Perkin-Elmer, Courtaboeuf, France). c-erbB-3 and
c-erbB-4 were positively correlated to each other (Spearman test) and
negatively correlated to EGFR. EGFR and c-erbB-2 were inversely
correlated to the presence of estradiol receptors (ER) and progesterone
receptors (PgR), and positively correlated to the histoprognostic
grading (HPG). Conversely, c-erbB-3 and c-erbB-4 were positively
correlated to the presence of ER and PgR, and inversely correlated to
the grading HPG. EGFR was inversely related (
2 test) to
the presence of ER and PgR, and positively associated with HPG. In
contrast, both c-erbB-3 and c-erbB-4 were inversely related to HPG, and
positively associated with the presence of ER and PgR. The expression
level of EGFR and c-erbB-2 was significantly higher in ER- and
PgR-negative tumors compared with ER- and PgR-positive tumors
(Student’s t test), and in tumors with higher grade
compared with tumors with lower grade. The expression level of c-erbB-3
and c-erbB-4 was significantly higher in ER- and PgR-positive tumors
compared with ER- and PgR-negative tumors and in tumors with lower
grade compared with tumors with higher grade. In overall survival
studies, Cox univariate analyses showed prognostic values of EGFR [
median; P = 0.026; risk ratio (RR), 1.6], c-erbB-3
( median; P = 0.0093; RR, 0.58), c-erbB-4 (
median; P = 0.0024; RR, 0.52), HPG, node
involvement, tumor diameter, ER, and PgR. In Cox multivariate analyses,
tumor diameter, ER, and PgR had a prognostic value. In relapse-free
survival studies, univariate analyses demonstrated prognostic values of
tumor diameter, node involvement, and c-erbB-4 (P =
0.015; RR, 0.65). These three parameters maintained their prognostic
value in multivariate analyses (c-erbB-4, P =
0.035; RR, 0.67). This study confirms that EGFR expression and c-erbB-2
expression are markers of tumor aggressiveness in breast cancer.
Conversely, we demonstrate that c-erbB-3 and c-erbB-4 elevated
expressions are associated with a better prognosis.
INTRODUCTION
The four members of the type I growth factor receptor gene family are the EGFR3 (1) , c-erbB-2 (2 , 3) also called HER2/neu (4) , c-erbB-3 (HER3; Refs. 5 and 6 ), and c-erbB-4 (HER4; Ref. 7 ).
Several lines of evidence suggest that this family of receptors is involved in breast cancer development and progression (8) . All four members are expressed in breast cancer cells in vitro. In primary breast cancer, because increased levels of EGFR (9) and c-erbB-2 (10) were first reported, several thousand cases have been studied, and the clinical significance of EGFR (11) and c-erbB-2 (12) has been extensively reviewed. The expression of both genes is associated with tumor aggressiveness and is related to a lower response to treatment. Recently, therapeutic approaches based on recombinant humanized monoclonal anti-c-erbB-2 antibodies (herceptin; Genentech, San Francisco, CA) have been developed (13) . As demonstrated by clinical trials (14) , these antibodies are well tolerated and clinically active in patients with metastatic breast cancer overexpressing c-erbB-2 and result in an increase in the objective clinical response rates when used in combination with chemotherapy. Elevated expression of c-erbB-3 has been described in breast cancers (15, 16, 17, 18) , but until now its association with classical prognostic factors and with clinical outcome has been poorly documented, and the results are somewhat controversial. With respect to c-erbB-4, several reports suggest that its expression is associated with the prognostically favorable ER phenotype and inversely correlated with EGFR expression (18 , 19) .
It is now well established that there are complex interactions between the members of the type I growth factor receptor family. In normal rat cell lines, the appropriate biological responsiveness to a particular ligand of this family is dependent on the levels of expression of specific combinations of the type I receptor (20) . In terms of cell growth, high expression of EGFR correlated with increased growth stimulation by EGF and betacellulin, whereas high levels of c-erbB-3 correlated with a greater mitogenic response to heregulin and sensory- and motor neuron-derived factor, with all of the cell lines expressing appreciable levels of c-erbB-2. The binding of a specific ligand to one of the members of the family leads to the formation of homo- and heterodimers. Although no ligand has been identified that binds directly to c-erbB-2, it is demonstrated that c-erbB-2 is the preferred heterodimerization partner for the three other receptors (21 , 22) .
These observations led us to investigate the expression of the type I growth factor receptor gene family in a large series of unselected human primary breast cancers with a real-time RT-PCR assay. We recently developed a one-step RT-PCR method for the routine quantification of c-erbB-2 mRNA expression using a 7700 ABI PRISM sequence detector system (Perkin-Elmer-Applied Biosystems; Ref. 23 ). The quantification of the PCR products is based on the TaqMan 5' nuclease assay (24 , 25) . We adapted this method to quantify the expression of the three other genes of the type I growth factor receptor family. The method was then applied to three human breast cancer cell lines, for which expression of the type I growth factor receptors has already been reported.
In the present article, we have analyzed the relationships between the levels of the mRNAs encoding these receptors and the classical clinical, pathological, and biological parameters as well as clinical outcome.
MATERIALS AND METHODS
Cell Lines.
All of the cell lines were purchased from the American Type Culture
Collection. MCF7 cells were cultured in MEM, SK-BR-3 cells were
cultured in RPMI 1640, and MDA-MB-468 cells were cultured in
Leibovitz’s L-15 medium. All media were supplemented with 10% FCS, 2
mM glutamine, 100 IU/ml penicillin, and 100 µg/ml
streptomycin. The cells were grown at 37°C in a humidified atmosphere
of 5% CO2 and collected at subconfluency.
For the quantification of the expression of the type I growth factor receptors, the cells were seeded at 10,000/cm2 in MEM supplemented with 10% FCS, 2 mM glutamine, 100 IU/ml penicillin, and 100 µg/ml streptomycin and were grown for 48 h. For each cell line, three 75-cm2 flasks were set up.
Patients.
This study involved 365 unselected breast tumor samples from patients
undergoing surgery for locoregional disease in the Center Oscar Lambret
(the Anticancer Center of the North of France) between May 1989 and
December 1991. The mean age of the patients was 58 years (range, 26–90
years). Patients were treated by segmentectomy when the tumor was <3
cm wide and by total mastectomy if the tumor was larger or centrally
located. Surgery was followed by radiation therapy. Node-positive
premenopausal patients and ER- and PgR-negative postmenopausal patients
received adjuvant treatment: six cycles of chemotherapy. The
node-positive ER- and PgR-positive postmenopausal patients received
tamoxifen for 2 years. Node-negative patients received no adjuvant
treatment.
The median duration follow-up of living patients was 77.6 months. The number of deaths was 94, and the number of relapses was 126.
ER and PgR Assay.
Both ER and PgR were determined by the dextran-coated charcoal method,
as previously described (26)
. Our laboratory is affiliated
to the European Organization for Research and Treatment of Cancer
Receptor Study Group, which undertook the quality control of the assays
(27)
.
Isolation of Total RNA.
The total RNA was isolated (RNeasy Mini Kit, Qiagen,
Courtaboeuf, France) from 40 mg of each tumor sample and from each
flask of the different cell lines. The disruption and the
homogenization of the tumor samples were performed using a Rotor-Stator
Homogenizer (Ribolyzer, Hybaid). The amount of extracted RNA was
quantified by measuring the absorbance at 260 nm. The purity of the RNA
was checked by the ratio between the absorbance values at 260 and 280
nm and ranged between 1.77 and 2.11, demonstrating the high quality of
the RNA. This was confirmed by electrophoresis of the RNA on 1.5%
agarose gel containing ethidium bromide.
Production of the RNA Standards.
We constructed RNA standards for each of the type I growth factor
receptor and for TBP. Each standard was obtained after
in vitro transcription (RiboMAX Large scale RNA Production
System T7, Promega, Charbonnières, France) of a cloned
fragment in a plasmid (pGEM-T Vector Systems, Promega), as previously
described (23)
.
PCR Primers and TaqMan Fluorogenic Probes.
The PCR primers and the TaqMan fluorogenic probes were designed using
the Primer Express software program (Demo version 1.0, Perkin-Elmer).
Their sequences are summarized in Table 1
. To confirm the total gene specificity
of the sequences chosen for the primers and probes, we performed
BLASTn (National Center for Biotechnology Information, Bethesda,
MD) searches against dbEST and the nonredundant set of GenBank,
European Molecular Biology Laboratory, and DNA Data Bank of Japan
database sequences. The primer pairs for each of the type I growth
factor receptor gene were designed to be unique when compared with the
sequence of the three other type I receptors. Each primer pair
amplified a region located on the extracellular domain of each type I
growth factor receptor.
|
We used the expression of the mRNA encoding the TBP gene, quantified with the primers and probe reported by Bièche et al. (28) , to normalize the level of expression of the type I growth factor receptors.
A nontemplate control was included in each experiment. All of the nontemplate controls, the standard RNA dilutions, and the tumor samples were assayed in duplicate.
Analysis and Expression of the Real-time RT-PCR Data.
The quantification of the starting quantity of a specific mRNA in an
unknown sample was performed by preparing a standard curve using known
dilutions of the corresponding standard RNA. For each dilution, the
Abi-Prism 7700 software generated a real-time amplification curve
constructed by relating the fluorescence signal intensity
(
Rn) to the cycle number. The Rn
value corresponded to the variation in the reporter fluorescence
intensity before and after PCR, normalized to the fluorescence of an
internal passive reference present in the buffer solution
(6-carboxy-x-rhodamine, a rhodamine derivative). The standard
curve was then generated on the basis of the linear relationship
existing between the Ct value (cycle threshold;
corresponding to the cycle number at which a significant increase in
the fluorescence signal was first detected) and the logarithm of the
starting quantity (29)
.
The level of mRNA expression of each type I growth factor receptor was expressed as a ratio between its own expression (in copies per µg total RNA) and TBP expression (in copies per µg total RNA) and was referred as normalized expression.
Statistical Analyses.
All of the statistical analyses were done using the SPSS Inc. software
(Version 8.0.1F). Relationships between qualitative variables
were determined using the 2
test (with Yates
correction when necessary). Correlations between parameters were
assessed according to the Spearman nonparametric test. Comparisons
between the levels of normalized expression of mRNA encoding the type I
growth factor receptors in different subgroup of tumors were performed
using the Student’s t test. OS and RFS were studied by
Kaplan-Meier method analysis. Comparison between curves was carried out
by the log rank test. The proportional hazard regression method of Cox
(30)
was used to assess the prognostic significance of
parameters taken in association. No time-dependent variable was
introduced.
RESULTS
Normalized Expression of the Type I Growth Factor Receptors in
Human Breast Cancer Cell Lines
The levels of expression of each type I growth factor receptor in
the MCF7, SK-BR-3, and MDA-MB-468 cells are summarized in Table 2
. The expression of EGFR was clearly the
highest in the MDA-MB-468 cells (30.43 ± 7.637). The highest
level of c-erbB-2 expression was clearly found in the SK-BR-3 cells
(35.04 ± 5.425). With respect to c-erbB-3, the expression was
similar in the MCF7 and the MDA-MB-468 cells (1.74 ± 0.38 and
1.346 ± 0.246, respectively), whereas the SK-BR-3 cells presented
higher levels (4.23 ± 0.724). The MCF7 cells exhibited the
highest c-erbB-4 expression (0.054 ± 0.019), whereas MDA-MB-468
and SK-BR-3 cells expressed very low levels (0.005 ± 0.0023 and
0.003 ± 0.001, respectively).
|
. The median value was, respectively,
0.11 for EGFR (range, 0.001–21), 0.17 for c-erbB-2 (range, 0.001–16),
3.45 for c-erbB-3 (range, 0.026–53), and 8.5
10-2 for c-erbB-4 (range, 0.0001–4).
|
Relationships with the Pathological, Clinical, and Biological
Parameters.
In this population, 73.9% of the tumors were ER positive, and
72.7% were PgR positive. The classical correlations between ER and PgR
(P < 0.001, r = 0.61), ER and age
(P < 0.001, r = 0.30), and PgR and age
(P = 0.019, r = 0.124) were observed.
c-erbB-2 was negatively correlated to ER (P = 0.003,
r = -0.154) and PgR (P = 0.004,
r = -0.152) and was positively correlated to HPG
(P = 0.014, r = 0.137). EGFR was
inversely correlated with ER (P < 0.001,
r = -0.47) and with PgR (P < 0.001,
r = -0.35) and positively with HPG (P < 0.001, r = 0.27). In contrast, c-erbB-3 and c-erbB-4
correlated positively with ER (c-erbB-3, P < 0.001,
r = 0.42; c-erbB-4, P < 0.001,
r = 0.53) and with PgR (c-erbB-3, P <
0.001, r = 0.33; c-erbB-4, P < 0.001,
r = 0.41) and negatively with HPG (c-erbB-3,
P < 0.001, r = -0.30; c-erbB-4,
P < 0.001, r = -0.48). The normalized
expression of EGFR mRNA was inversely related to the presence of ER and
PgR and positively associated with HPG, using the
2
test (Table 3)
. No relationship was observed between
the normalized expression of c-erbB-2 mRNA and the classical
pathological, clinical, and biological parameters. The normalized
expression of mRNAs for both c-erbB-3 and c-erbB-4 were positively
associated with the presence of ER and PgR and inversely related to the
HPG (Table 2)
. Furthermore, elevated c-erbB-4 expression had a
significantly higher incidence in lobular than in ductal carcinomas,
and larger tumors had a lower level of expression of c-erbB-4 mRNA
(Table 3)
.
|
a) and in PgR-negative than
in PgR-positive tumors (EGFR, P = 0.028; c-erbB-2,
P = 0.017; Fig. 2
b). The mean level of the
expression of c-erbB-2 was also higher in tumors of higher grade
(P = 0.032; Fig. 2
c). In contrast, the mean
level of the expression of mRNA encoding c-erbB-3 and c-erbB-4 was
significantly lower in ER-negative than in ER-positive tumors
(c-erbB-3, P < 0.001; c-erbB-4, P <
0.001; Fig. 2
a), in PgR-negative tumors than in
PgR-positive tumors (c-erbB-3, P < 0.001; c-erbB-4,
P < 0.001; Fig. 2
b), and than in
tumors of higher grade (c-erbB-3, P < 0.003;
c-erbB-4, P < 0.001; Fig. 2
c).
|
Overall Survival.
For each of the type I growth factor receptor, three cutoff
points (i.e., median value, lower and upper quartiles) were
tested for their ability to distinguish two populations of tumors with
different prognoses. The best threshold for prognosis was the median
value for EGFR (0.11), c-erbB-3 (3.45), and c-erbB-4 (8.5
10-2). However, for EGFR and c-erbB-4, the upper
quartile also allowed us to distinguish two populations of different
prognoses. Shorter OS was found in patients with elevated normalized
expression of EGFR mRNA (Fig. 3)
. In
contrast, longer OS was observed in patients with elevated expression
of c-erbB-3 (Fig. 4)
and c-erbB-4 mRNAs
(Fig. 5)
. HPG, node involvement, tumor
size, ER, and PgR were also prognostic factors (Table 4)
. The normalized expression of c-erbB-2
mRNA was not a prognostic factor whatever the positive threshold
chosen. In multivariate analyses, when combining the parameters that
have a prognostic value in univariate analyses, tumor diameter, ER, and
PgR maintained their statistically significant prognostic value (Table 5)
.
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.
Tumor size and node involvement were also prognostic factors. On the
other hand, neither HPG, ER, PgR, c-erbB-3, nor EGFR was a prognostic
factor (Table 4)
. In multivariate analyses, the statistically
significant prognostic value of c-erbB-4, tumor size, and node
involvement was preserved (Table 5)
.
|
In this study, we analyzed the expression of type I growth factor receptor gene family in a large series of primary breast cancers to establish the relationships between expression and the pathological, clinical, and biological parameters and the clinical outcome. The expression was quantified with a real-time RT-PCR assay. We recently developed a one-step RT-PCR method for the routine quantification of c-erbB-2 expression using a 7700 ABI PRISM sequence detector system (Perkin-Elmer-Applied Biosystems; Ref. 23 ). On the basis of this experience, we adapted the method to quantify the expression of the three other genes of the type I growth factor receptor family. The TBP gene was used to normalize the expression of the type I growth factor receptors. The use of TBP as a control RNA was relevant in these studies investigating prognosis because we observed that its expression was not associated with tumor aggressiveness (data not shown), in contrast with the widely used glyceraldehyde-3-phosphate dehydrogenase gene (31) .
With respect to the three cell lines analyzed in this study, the expression of the type I growth factor receptors was found to be in agreement with previous reports. Among these cell lines, the MDA-MB-468 cells have been shown to express the highest levels of EGFR (32) , and the SK-BR-3 cells are known to express the highest levels of both c-erbB-2 (32 , 33) and c-erbB-3 (15) . The MCF7 cells have been reported to present higher levels of c-erbB-4 expression than the SK-BR-3 and MDA-MB-468 cells using Northern blot (7) , although comparable levels of expression have been found in SK-BR-3 and MCF7 cells by RT-PCR (34) .
We observed differences between the expression level of the four genes in a series of 365 primary breast cancers. c-erbB-2 and EGFR exhibited similar levels of expression. In contrast, the level of expression of c-erbB-2 was lower and higher than that of c-erbB-3 and of c-erbB-4, respectively. The comparison between these results and those of the literature is difficult. Most studies analyze the expression of these receptors at the level of the protein using immunohistochemistry and do not analyze simultaneously the level of expression of the four receptors. Recently, Sundaresan et al. (20) quantified the expression of the type I growth factor receptors using real-time quantitative RT-PCR in five murine cell lines from various tissues, except mammary gland. Interestingly, their results showed that c-erbB-4, when detectable, presented lower levels of mRNA expression, a finding that is in keeping with our observations in the breast cancer samples.
The present results, demonstrating the positive correlation between the normalized expression of mRNAs encoding c-erbB-3 and c-erbB-4 and the negative correlation between the normalized expression of mRNAs encoding c-erbB-3 and c-erbB-4 with that encoding EGFR, concur with those recently reported by Knowlden et al. (18) . We found no correlation between normalized expression of c-erbB-2 mRNA and those of the three other receptors. It is noteworthy that, as yet, there is no agreement on the relationship between the expression of c-erbB-2 and those of both EGFR (11) and c-erbB-3 (12) .
With respect to the clinical, histological, and biological parameters, elevated EGFR expression was inversely related to the presence of ER and PgR, whereas it was positively associated with HPG. Accordingly, Klijn et al. (11) observed that most studies indicated a negative relationship between EGFR and steroid receptor status, showing that EGFR positivity is twice as high in ER or PgR-negative tumors as in ER or PgR-positive tumors. Moreover, these authors also reported that there was a likely association between high EGFR levels and poor tumor differentiation and grade. We found an inverse relationship between the normalized expression of c-erbB-2 mRNA and the presence of ER and PgR, whereas it was positively associated with HPG. In agreement with these results, we previously reviewed the biological and clinical data on c-erbB-2 in breast cancer (12) , and despite the discrepancies observed between the different studies, we pointed out several associations between c-erbB-2 positivity and the classical clinicopathological parameters, including the lack of steroid receptors, the histological subtypes of mammary tumors, worse histological and nuclear grades, aneuploidy, and high rate of proliferation. It is noteworthy that recently, Knowlden et al. (18) evaluated the mRNA expression of the type I growth factor receptor in 47 primary breast cancers by RT-PCR. Interestingly, they indicated that although RT-PCR was also performed using specific c-erbB-2 primers, the data regarding this marker were not included in their study because no correlations were observed with the range of parameters examined. Concerning c-erbB-3 and c-erbB-4, the positive association observed between elevated expression of these receptors and the presence of ER and PgR is in agreement with the result of Knowlden et al. (18) . We also found an inverse relationship with HPG. Such results suggest that both c-erbB-3- and c-erbB-4-elevated mRNA expressions could be biological markers of a more differentiated phenotype, as already reported for c-erbB-4 mRNA and protein expression (35) . Moreover, these authors recently demonstrated that c-erbB-4 nuclear immunoreactivity was frequent in invasive breast cancers and seemed to be associated with a better differentiated phenotype (36) . Concerning c-erbB-3 protein expression, however, some results do not support the association with differentiation (15, 16, 17 , 37) .
In the prognostic analyses, we found that c-erbB-4 had a prognostic value in terms of OS and RFS in the Cox univariate analyses. To our knowledge, this is the first report demonstrating a prognostic value of c-erbB-4 mRNA expression in a large series of breast cancers. Recently, in contrast with our findings, no significant associations were found between disease-free interval or survival and c-erbB-4 protein expression in a series of 127 primary invasive breast cancers (38) . EGFR and c-erbB-3 were also prognostic indicators in OS analyses, but they did not appear to be prognostic indicators in RFS. Accordingly, EGFR expression is known to be associated with a poor prognosis (11) . The prognostic value of c-erbB-3 is still controversial. In agreement with our results, Knowlden et al. (18) reported that patients with ER- and c-erbB-3-positive tumors were most likely to benefit from endocrine measures. This suggests that increased c-erbB-3 could be associated with the prognostically favorable ER phenotype. In contrast, Travis et al. (17) reported that patients whose tumors presented high expression of c-erbB-3 protein were more likely to develop local recurrence. Finally, some authors found no relationship with survival (15 , 16) . In the present study, c-erbB-2 was not a prognostic factor. In a review of the literature (12) , we pointed out 5 of 19 studies with such results. Recently, Bièche et al. (28) failed to find a prognostic value of c-erbB-2 mRNA expression in a series of 134 breast cancers. The multivariate Cox analyses combining EGFR, c-erbB-3, c-erbB-4, and the other classical biological and clinical prognostic factors revealed that none of these type I growth factor receptors maintained their prognostic value on OS. Nevertheless, c-erbB-4 was found to be an independent prognostic factor on RFS, together with tumor diameter and node involvement.
In conclusion, the present study confirms that the expression of EGFR and c-erbB-2 is a marker of tumor aggressiveness in breast cancer. Conversely, we demonstrate that c-erbB-3 and c-erbB-4 elevated expressions are associated with a better prognosis.
ACKNOWLEDGMENTS
We thank Dr. Dave Fernig (School of Biological Sciences, University of Liverpool, England, United Kingdom) for critical reading of the manuscript.
FOOTNOTES
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Supported by the Ligue Nationale Contre le
Cancer (LNCC, Paris), the Comité Départemental du Nord de
la LNCC (Lille), and the Comité Flandres-Artois du Groupement des
Entreprises Françaises pour la Lutte contre le Cancer (Lille).
The Laboratoire d’Oncologie Moléculaire Humaine belongs to, and
is supported by, the Institut Fédératif de Recherche 22
"Biologie et Pathologie des régulations cellulaires" (Lille,
France). V. P. is the recipient of a fellowship from the Association
pour la Recherche sur le Cancer (Villejuif). 
2 To whom requests for reprints should be
addressed, at Laboratoire d’Oncologie Moléculaire Humaine,
Centre Oscar Lambret, 3 rue Frédéric Combemale, BP 307,
59020 Lille Cédex, France. Phone: 33-3-20-29-59-59,
extension 5233; Fax: 33-3-20-29-59-62; E-mail: f-revillion{at}o-lambret.fr
3 The abbreviations used are: EGFR, epidermal
growth factor receptor; RT, reverse transcription; TBP, TATA box
binding protein; ER, estradiol receptor; PgR, progesterone receptor;
OS, overall survival; RFS, relapse-free survival; HPG, histoprognostic
grading.
Received 4/21/00; revised 8/10/00; accepted 8/16/00.
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F. Revillion, M. Charlier, V. Lhotellier, L. Hornez, S. Giard, M.-C. Baranzelli, J. Djiane, and J.-P. Peyrat Messenger RNA expression of leptin and leptin receptors and their prognostic value in 322 human primary breast cancers. Clin. Cancer Res., April 1, 2006; 12(7 Pt 1): 2088 - 2094. [Abstract] [Full Text] [PDF]
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H. Arbach, V. Viglasky, F. Lefeu, J.-M. Guinebretiere, V. Ramirez, N. Bride, N. Boualaga, T. Bauchet, J.-P. Peyrat, M.-C. Mathieu, et al. Epstein-Barr Virus (EBV) Genome and Expression in Breast Cancer Tissue: Effect of EBV Infection of Breast Cancer Cells on Resistance to Paclitaxel (Taxol) J. Virol., January 15, 2006; 80(2): 845 - 853. [Abstract] [Full Text] [PDF]
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F. Gizard, R. Robillard, O. Barbier, B. Quatannens, A. Faucompre, F. Revillion, J.-P. Peyrat, B. Staels, and D. W. Hum TReP-132 Controls Cell Proliferation by Regulating the Expression of the Cyclin-Dependent Kinase Inhibitors p21WAF1/Cip1 and p27Kip1 Mol. Cell. Biol., June 1, 2005; 25(11): 4335 - 4348. [Abstract] [Full Text] [PDF]
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T. T. Junttila, M. Sundvall, M. Lundin, J. Lundin, M. Tanner, P. Harkonen, H. Joensuu, J. Isola, and K. Elenius Cleavable ErbB4 Isoform in Estrogen Receptor-Regulated Growth of Breast Cancer Cells Cancer Res., February 15, 2005; 65(4): 1384 - 1393. [Abstract] [Full Text] [PDF]
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A. Skildum, E. Faivre, and C. A. Lange Progesterone Receptors Induce Cell Cycle Progression via Activation of Mitogen-Activated Protein Kinases Mol. Endocrinol., February 1, 2005; 19(2): 327 - 339. [Abstract] [Full Text] [PDF]
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A. Chotteau-Lelievre, F. Revillion, V. Lhotellier, L. Hornez, X. Desbiens, V. Cabaret, Y. de Launoit, and J.-P. Peyrat Prognostic Value of ERM Gene Expression in Human Primary Breast Cancers Clin. Cancer Res., November 1, 2004; 10(21): 7297 - 7303. [Abstract] [Full Text] [PDF]
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H. Dote, S. Toyooka, K. Tsukuda, M. Yano, M. Ouchida, H. Doihara, M. Suzuki, H. Chen, J.-T. Hsieh, A. F. Gazdar, et al. Aberrant Promoter Methylation in Human DAB2 Interactive Protein (hDAB2IP) Gene in Breast Cancer Clin. Cancer Res., March 15, 2004; 10(6): 2082 - 2089. [Abstract] [Full Text] [PDF]
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G. Atalay, F. Cardoso, A. Awada, and M. J. Piccart Novel therapeutic strategies targeting the epidermal growth factor receptor (EGFR) family and its downstream effectors in breast cancer Ann. Onc., September 1, 2003; 14(9): 1346 - 1363. [Abstract] [Full Text] [PDF]
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S. Toyooka, K. O. Toyooka, K. Miyajima, J. L. Reddy, M. Toyota, U. G. Sathyanarayana, A. Padar, M. S. Tockman, S. Lam, N. Shivapurkar, et al. Epigenetic Down-Regulation of Death-associated Protein Kinase in Lung Cancers Clin. Cancer Res., August 1, 2003; 9(8): 3034 - 3041. [Abstract] [Full Text] [PDF]
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J. S. Ross, J. A. Fletcher, G. P. Linette, J. Stec, E. Clark, M. Ayers, W. F. Symmans, L. Pusztai, and K. J. Bloom The HER-2/neu Gene and Protein in Breast Cancer 2003: Biomarker and Target of Therapy Oncologist, August 1, 2003; 8(4): 307 - 325. [Abstract] [Full Text] [PDF]
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