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Advances in Brief |
Ernest Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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vß3
integrin that is differentially expressed in HRG-positive cells, and
have shown that it is expressed in all of the invasive and metastatic
breast cancer cell lines tested. Preliminary evaluation of Cyr61
expression in breast tumor biopsies revealed expression of Cyr61 in
about 30% of invasive breast carcinomas. Significantly, we
demonstrated that Cyr61 is a downstream effector of HRG action, because
a Cyr61-neutralizing antibody abolished the ability of HRG-expressing
cells to migrate in vitro. Furthermore, we have shown
that HRG-expressing cells denote higher levels of
vß3 expression, and we have established
that Cyr61 action is mediated, at least in part, through its receptor
vß3, because a functional blocking
antibody of the vß3 blocked the Matrigel
outgrowth of HRG-expressing cells. These results strongly suggest that
Cyr61 is necessary for HRG-mediated chemomigration and that Cyr61 plays
a functional role in breast cancer progression, possibly through its
interactions with the vß3 receptor. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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With this in mind, we have isolated and identified the human homologue
of a mouse immediate-early response gene, Cyr61,
differentially expressed in ER-negative, HRG-positive breast cancer
cells. Cyr61 is a secreted cysteine-rich protein that is associated
with the cell surface and the extracellular matrix
(5)
. Cyr61 mediates cell adhesion, migration, and
angiogenesis (6
, 7)
. In this report, we establish that
Cyr61 is coexpressed with HRG in all of the metastatic breast cancer
cell lines tested, its expression is inversely correlated with ER
expression, and it is associated with HRG-induced breast cancer
chemomigration and metastasis, possibly through interactions with the
vß3 integrin receptor.
Furthermore, we establish that Cyr61 was expressed in about 30% of
invasive breast cancer tumor biopsies, implying a possible role in
breast cancer progression.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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Plasmids and Generation of Riboprobes
A Cyr61 riboprobe plasmid was constructed by cloning a PCR
fragment of Cyr61 cDNA into the pCRII TA cloning vector (Invitrogen).
The sequence of primers used to generate the Cyr61 fragments was as
follows: (a) forward primer, 5'-TGTGGAACTGGTATCTCCACACGA-3'
(nucleotides 727–750); and (b) reverse primer,
5'-TCTTTTCACTGAATATAAAATTAAAA-3' (nucleotides 1739–1764). The Cyr61
riboprobe construct was sequenced using Sequenase v.2.0 with
35S-labeled dCTP. Radioactive riboprobe was
prepared by linearizing the plasmid with the restriction enzyme
DdeI, which generated a 524-bp fragment, and followed by
reverse transcription in vitro using the SP6 RNA polymerase
in the presence of [32P]UTP. The riboprobe
plasmid of GAPDH was kindly provided by Dr. Francis Kern (University of
Alabama, Birmingham, AL). Radiolabeled GAPDH riboprobe was generated
using T7 RNA polymerase as described above, except that it was
linearized by the restriction enzyme BamHI.
RNase Protection Assay
Total RNA was extracted by Tripure isolation solution (Roche
Molecular Biochemicals) and quantified by spectrophotometry. RNA (30
µg) was hybridized with 100,000 cpm of
32P-labeled Cyr61 riboprobe for 12–16 h at
50°C. 32P-labeled GAPDH riboprobe (10,000 cpm)
was added to each sample as an internal control. Hybridized RNA samples
were digested with 25 µg of RNase A for 30 min at 28°C. The
reaction was terminated by incubating with proteinase K (250 µg/ml)
and 0.5% SDS for 15 min at 37°C. After phenol extraction, RNA
samples were coprecipitated with 10 µg of yeast tRNA in absolute
ethanol. RNA was redissolved in a denaturing loading buffer and
resolved by electrophoresis on a 6% polyacrylamide-urea gel. Protected
fragments of Cyr61 (305 bp) and GAPDH (100 bp) were visualized by
autoradiography. [32P]dCTP-end-labeled
pBR322/MspI (New England Biolabs) was used as a molecular
weight marker.
Western Blot Analysis
Cyr61 Present in Conditioned Media.
Subconfluent human breast cancer cells were maintained in serum-free
media for 3–4 days. The conditioned media were collected, and the
Cyr61 protein was purified by heparin affinity chromatography. The
column was washed with 0.3–0.6 M NaCl in 10 mM
Tris-HCl (pH 7.5). The Cyr61 protein was eluted at 0.9
M NaCl and desalted by PD-10 Sephadex G25M
columns (Amersham-Pharmacia). The eluted fractions were concentrated
(10x) and resolved by 12% Tris-glycine SDS-PAGE. The separated
proteins were electroblotted onto a Hybond enhanced chemiluminescence
nitrocellulose membrane (Amersham-Pharmacia). The blotted membrane was
blocked overnight at 4°C with 5% (w/v) BSA in Tris-buffered saline
containing 0.5% Tween 20 (TBST) and incubated with the rabbit
anti-Cyr61 polyclonal antibody (1:5,000 dilution) for 1 h at room
temperature. After three washes with TBST, the blot was incubated with
a 1:10,000 dilution of horseradish peroxidase-linked donkey antirabbit
IgG secondary antibody. The Cyr61 protein was detected by the enhanced
chemiluminescence reaction using Hyperfilm (Amersham-Pharmacia).
Cyr61 Present in Breast Cancer Tumor Specimens.
Breast tumor specimens were lysed in radioimmunoprecipitation assay
buffer [50 mM Tris-HCl (pH 8.0), 150 mM NaCl,
0.5 mM EDTA, 1% NP40, 0.5% sodium deoxycholate, 0.1%
SDS, and 1 mM DTT] with protease inhibitors (10 µg/ml
leupeptin, 10 µg/ml aprotinin, 0.5 mM sodium
orthovanadate, and 1 mM phenylmethylsulfonyl fluoride).
Protein concentration was determined by a Micro BCA detection reagent
kit (Pierce). Equal amounts of proteins were loaded and separated by
SDS-PAGE followed by Western blot analysis as described above.
Immunohistochemical Staining
Formalin-fixed paraffin-embedded breast tumor sections were
deparaffinized in xylene and hydrated in a graded alcohol series.
Slides were quenched for endogenous peroxidase activity in the presence
of 0.3% H2O2 for 30 min
and blocked with 10% (v/v) horse serum for 30 min. Slides were then
incubated with a polyclonal anti-Cyr61 antibody (1:5000) overnight at
4°C. The sections were washed in PBS before the incubation with a
biotinylated antirabbit IgG secondary (1:200) antibody for 30 min. The
sections were then incubated with an avidin-biotin complex (VECTASTAIN
Elite ABC reagent; Vector Laboratories) for 30 min, and the reaction
was developed in the presence of hydrogen peroxide and
3,3'-diaminobenzidine tetrahydrochloride. The slides were
counterstained with hematoxylin solution and mounted with the aqueous
Crystal mount media.
Chemomigration and Chemotaxis Assays
Boyden chamber chemomigration assays were performed using a
48-well chemotaxis chamber (Neuro Probe). Breast cancer cells (20,000
cells/well) were plated onto the upper chambers in triplicate or
quadruplicate onto a 12 µm polycarbonate filter membrane coated with
collagen (Becton Dickinson). The conditioned media derived from NIH3T3
fibroblast culture was used as a chemoattractant in the lower chambers.
Cells were incubated at 37°C in a humidified 5%
CO2 atmosphere for 16 h. After the
incubation, the membrane was removed from the chamber. The cells on the
top surface were removed, and the cells on the bottom side of the
membrane were fixed in methanol and stained with a Diff-Quick Stain
kit. Membranes were then mounted onto glass slides, and the cells that
migrated through the pores to the opposite side of the membrane (bottom
side) were quantified using a light microscope.
Matrigel Outgrowth Assay
Cells (5,000 cells/well) were mixed with 150 µl of Matrigel
(Becton Dickinson) and plated in triplicate onto the Matrigel-coated
12-well plates for 1 h at 37°C. Cells were then cultured in the
media containing the indicated concentrations of antibodies for 7–10
days. The pattern of the cells’ outgrowth in Matrigel matrix
was examined and photographed using a phase-contrast microscope.
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Results and Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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. To determine whether the protein was also selectively
expressed, we performed Western blot analysis and immunohistochemistry
using an anti-Cyr61 polyclonal antibody. As shown in Fig. 1B
, Cyr61 protein expression was observed in the MCF-7/HRG
cells but not in the vector control cells. These studies were performed
using cells cultured under serum-depleted conditions.
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. Similar features were observed in all
of the tumors examined. As can be seen in Fig. 1C
, Cyr61
expression was very predominant in MCF-7/HRG-derived tumors
(right panel). Expression of the Cyr61 protein was localized
to the cytoplasm of the tumor cells, whereas only a weak staining of
Cyr61 was observed in tumors derived from MCF-7/V cells supplemented
with E2 (left panel). Once again, our data demonstrate a
differential expression of Cyr61 in HRG-expressing cells. We mapped the human Cyr61 gene to chromosome 1p (data not shown), consistent with previous studies showing the localization of Cyr61 to chromosome 1p22.3 (8 , 9) . Abnormalities of chromosome 1p have correlated with ER negativity and a poor prognosis in breast cancer (10) and other malignancies (11, 12, 13) .
It has been shown that murine Cyr61 is regulated by 12-O-tetradecanoylphorbol-13-acetate in the liver (14) , as well as by E2 and Tam in the uterus (15) . We have shown that the human homologue of Cyr61 is regulated by E2 and several antiestrogens including Tam and ICI 182,780 in ER-positive breast cancer cells.6 The induction of Cyr61 was most significant in MCF-7 cells [up to a 10–12-fold increase by 6 h of treatment with E2 (10-9 M) or 3 h of treatment with ICI 182,780 (10-7 M)] and to about a 5–6-fold increase with Tam (10-7 M). On the other hand, the up-regulation of Cyr61 was not significant in HRG-expressing cells, with an increase of only 1.5–2-fold by any of the treatments (data not shown). These results are consistent with our published data demonstrating that HRG promotes an estrogen-independent phenotype and that HRG blocks ER function resulting in MCF-7/HRG cells that fail to respond to E2 and the consequential inability of E2 to induce the expression of E2-regulated genes.
Cyr61 Is Overexpressed in HRG-positive, ER-negative Breast Cancer
Cell Lines.
To assess whether up-regulation of Cyr61 expression was a result of HRG
overexpression in MCF-7/HRG cells or whether it was a common theme
occurring in breast cancer cells, we examined its expression in many
human breast cancer cell lines. Basal level of Cyr61 expression was
measured in cells cultured under serum-depleted conditions to prevent
the influence of E2 on Cyr61 expression. As shown in Fig. 1, B and D
, a tight correlation between Cyr61 mRNA
and protein expression exists in all of the cell lines tested. Cyr61 is
highly expressed in MDA-MB-231, HS578T, BT549, and MCF-7/HRG cells, all
of which are HRG-expressing and ER-negative cells, but it is low or
undetectable in cells that do not express HRG and are ER-positive,
including MCF-7, ZR75B, T47D, and BT474 cells. These studies were
performed by RNase protection assays and by Western blot analysis in
which a secreted Mr 45,000
protein derived from conditioned media was detected using an anti-Cyr61
polyclonal antibody.
Our data indicate that a high level of Cyr61 expression correlates with
HRG expression and inversely correlates with ER expression, response to
E2, and sensitivity to antiestrogens (16)
. Moreover, the
expression of Cyr61 strongly correlates with vimentin expression, a
known marker for invasiveness (17)
, and is associated with
the ability of breast cancer cells to invade in vitro and
metastasize in vivo. On the other hand, low to undetectable
levels of Cyr61 expression were seen only in the HRG-negative,
ER-positive, E2-dependent, antiestrogen-sensitive breast cancer cells.
These data are summarized in Table 1
. Taken together, these data show that Cyr61 expression is associated
with HRG expression and is apparently linked to breast cancer
progression. Because Cyr61 is an early response gene,
it could be argued that its expression would be up-regulated in rapidly
proliferating cells. Thus, it is critical to establish that
up-regulation of Cyr61 in MCF-7/HRG cells is not attributable to a
proliferative advantage of these cells. Cell cycle analysis by flow
cytometry demonstrated that no differences in cell cycle distribution
were observed between the MCF-7/HRG cells and the parental MCF-7 cells
(18)
.
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. Total cell lysates of MDA-MB-231 and MCF-7 were used as
positive and negative controls, respectively. It is noteworthy that
Cyr61 protein expression was low in cell lysates of MDA-MB-231, because
Cyr61 is mostly secreted to the cultured media. Additional
studies revealed that Cyr61 was detected in about 30% of breast tumor
specimens (n = 55) by immunohistochemistry
(Fig. 2B)
. Cyr61 staining was demonstrated to be specific
because it was completely blocked in the presence of excess recombinant
Cyr61 protein (data not shown). No staining was observed in normal
components of the biopsies. These data suggest that in at least 30% of
these tumors, Cyr61 may be required for survival; therefore, it may be
strongly implicated in breast cancer progression.
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. No effect was observed when a control IgG antibody was
used under the same conditions and concentrations. Similar results were
observed in other invasive, HRG-expressing breast cancer cells, such as
MDA-MB-231, HS578T, and BT549 (data not shown). These studies suggest,
for the first time, a possible association between the increase in
Cyr61 expression and the invasive potential triggered by HRG.
Additional studies are required to assess the direct association
between Cyr61 and HRG and their joint action resulting in breast cancer
progression. Of note, the anti-Cyr61neutralizing antibody had no
effect on MCF-7 cells. It is important to note that MCF-7 cells do not
migrate through collagen.
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vß3 Integrin Receptor Is
Involved in Cyr61-Mediated Breast Cancer Progression.vß3 integrin
(19)
, we speculated whether Cyr61 requires expression of
vß3 for its action.
Thus, we assessed the level of
vß3 expression in
MCF-7/HRG cells and showed that the level of
vß3 was augmented in
MCF-7/HRG cells compared with the MCF-7/V cells (data not shown), as
determined by immunofluorescence staining using an
anti-vß3 antibody on
cultured cells. We then speculated that if the action of Cyr61 is
mediated through the
vß3 receptor, it is
plausible that blockage of the
vß3 integrin will
modulate the growth characteristics of MCF-7/HRG cells. Thus, Matrigel
outgrowth and migration studies were performed in the presence and
absence of an anti-vß3
functional blocking antibody. We determined that this antibody
specifically blocked the Matrigel outgrowth of HRG-expressing cells in
a dose-dependent manner (Fig. 3B)
. No effects were observed
when control IgG was used. Similar inhibitory effects of the
anti-vß3 antibody were
seen in HRG-positive MDA-MB-231 cells (data not shown).
The results indicated that the functional
vß3 integrin is
required for maintaining the invasive capacity of HRG-expressing cells,
and that the aggressive phenotypes induced by HRG are mediated, in part
if not entirely, by Cyr61 and its receptor,
vß3 integrin. Because
Cyr61, an angiogenic factor, and its receptor,
vß3, are both induced
in the MCF-7/HRG cells, it is tempting to postulate that these factors
are involved in the increased neovascularization that we have observed
in the tumors formed by MCF-7/HRG cells in athymic nude
mice.6
The exact mechanism by which HRG
promotes an aggressive breast cancer phenotype is still unknown.
However, the identification of Cyr61 expression in breast cancer tumor
progression is of great significance, especially because its receptor,
the vß3 integrin, was
recently shown to be a good prognostic indicator in breast cancer
(20
, 21)
. Studies are under way to determine whether
ectopic expression of Cyr61 alone, in HRG-negative cells, is sufficient
and/or necessary to confer some biological activities induced by HRG,
such as loss of E2 response, acquisition of antiestrogen resistance,
and chemomigration.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by a grant from the NIH (Contract No.
DK49049) and by the Department of Energy under Contract No.
DE-AC03-76SF00098 (to R. L.) and the Breast Cancer Research Program
Postdoctoral Traineeship from the Department of Defense (to
M-S. T.). 
2 Present address: PE Biosystem, 850 Lincoln
Center Drive, Foster City, CA 94404.
3 Present address: Institute for Medicine and
Engineering, University of Pennsylvania, 1170 Vagelos Research
Laboratories, 3340 Smith Walk, Philadelphia, PA 19104.
4 To whom requests for reprints should be
addressed, at Lawrence Berkeley National Laboratory, University of
California, 1 Cyclotron Road, Berkeley, CA 94720. Phone:
(510) 486-6874; Fax: (510) 486-6816; E-mail: rlupu{at}lbl.gov
5 The abbreviations used are: E2, estradiol; Tam,
tamoxifen; ER, estrogen receptor; HRG, heregulin; GAPDH,
glyceraldehyde-3-phospate dehydrogenase.
6 M. S. Tsai, E. Gilad, M. Cardillo, and R.
Lupu. Heregulin (HRG) promotes tumor formation, manuscript in
preparation.
Received 4/24/00. Accepted 9/ 1/00.
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REFERENCES |
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TopABSTRACTIntroductionMaterials and MethodsResults and DiscussionREFERENCES |
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