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Expression Is Associated with the Metastatic Phenotype in Breast Cancer1
Departments of Anatomy and Cell Biology [D. A. K., L. M. G. G., E. A. S., V. A. O., M. J. C. H.] and Biochemistry [L. L. W.], College of Medicine, University of Iowa Cancer Center, University of Iowa, Iowa City, Iowa 52242-1109; Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27514-7525 [R. A. L.]; and Institute of Cell and Molecular Biology, University of Edinburgh, Edinburgh Scotland, United Kingdom EH9 3JR [A. M. A., W. C. E.]
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ABSTRACT |
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expression in MDA-MB-231 breast
carcinoma cells (highly invasive/metastatic) compared with MCF-7 cells
(poorly invasive/nonmetastatic). In this study, we demonstrate that
HP1Hs, but not
HP1Hsß or
HP1Hs
, is
down-regulated at the mRNA and protein levels in highly
invasive/metastatic breast cancer cell lines. In agreement, little to
no nuclear HP1Hs staining was observed in these cell
lines. In contrast, poorly invasive/nonmetastatic cell lines showed
HP1Hs localization to the nucleus and nuclear membrane.
Transfection of MDA-MB-231 cells with a green fluorescent
protein-HP1Hs expression vector decreased their ability
to invade a collagen IV/laminin/gelatin matrix compared with green
fluorescent protein-transfected controls. Consistent with the cell
culture studies, immunohistochemical analysis of HP1Hs
protein localization in distant metastatic tissues from breast cancer
patients revealed a decrease in the staining intensity and percentage
of cells expressing HP1Hs in seven of nine distant
metastatic lesions compared with normal mammary and primary tumors.
These results demonstrate a role for HP1Hs in breast
cancer invasion and metastasis. Given the role of HP1 in
transcriptional silencing in Drosophila, we propose a
model in which HP1Hs normally silences genes involved in
breast cancer invasion and metastasis. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Direct evidence that HP1 is involved in gene silencing stems from experiments in which the levels of HP1 were modulated. Mutations in the gene encoding HP1 are homozygous lethal in Drosophila (5) . HP1 heterozygotes show a loss of silencing of transgenes at centric locations, which correlates with a more "open" (euchromatic-like) chromatin structure (6) . In contrast, HP1 overexpression leads to an increase in gene silencing (5 , 7) . In mice, increased silencing of a centric transgene was observed upon overexpression of a mouse HP1-like protein, M1 (8) . Therefore, gene expression appears to be sensitive to HP1 dosage (7) ; however, the exact mechanism by which HP1 exerts its suppressive effect is not known.
Three HP1-like proteins have also been identified in humans.
HP1Hs and HP1Hsß
localize to pericentric heterochromatin and minor sites within
euchromatic regions (9, 10, 11)
. In contrast,
HP1Hs localizes primarily to euchromatin
(10)
. Drosophila and mammalian HP1 interact
with many different types of proteins (5)
, and recent
evidence demonstrates that mammalian HP1 is part of a transcriptional
repression complex (8
, 12, 13, 14)
. Taken together, these
results suggest that the function of mammalian HP1-like gene products
is similar to that of Drosophila HP1 and may play a key role
in the regulation of genes essential for proper development.
We demonstrate here that HP1Hs mRNA and
protein expression are down-regulated in breast cancer cells with an
invasive/metastatic phenotype. HP1Hs protein
expression was decreased in seven of nine metastatic tumor tissues from
breast cancer patients, and stable transfection of the
HP1Hs gene into MDA-MB-231 cells
decreased their in vitro invasive potential. These data
suggest that a reduction in HP1Hs expression
is directly associated with tumor cell invasion and metastasis.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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RNA Isolation and Northern Hybridization Analysis.
Total RNA was isolated from breast cancer cell lines using Trizol RNA
isolation reagent (Life Technologies, Inc.) according to the
manufacturer’s specifications. Northern blot analysis of
HP1Hs mRNA expression was
performed on breast cancer cell lines of different invasive and
metastatic potential, as described previously (15)
. Each
experiment was repeated twice with similar results.
Semiquantitative RT-PCR Analysis.
Reverse transcription of total RNA from breast cancer cell lines was
performed using the Advantage PCR kit according to the manufacturer’s
instructions (Clontech, Palo Alto, CA). PCR amplifications were
performed with HP1Hsß- and
HP1Hs-specific primers
(HP1Hsß forward primer,
5'-AAAACAAGAAGAAAGTAGAGGAGGTGC-3';
HP1Hsß reverse primer,
5'-CAGATGTGACAGGGGCTGG-3'; HP1Hs
forward primer, 5'-GCGTTTCTTAAACTCTCAGAAAGC-3';
HP1Hs reverse primer,
5'-TTATTATTTGTTCAAAGTAACCAGTGCT-3'). Annealing temperature and the
number of amplification cycles were optimized at 62°C and 28 cycles,
respectively, using cDNA from MCF-7 and MDA-MB-231 cells. PCR
amplification reactions were performed in a Robocycler gradient 96
thermocycler (Stratagene, La Jolla, CA) under the following conditions:
1 cycle at 94°C for 1 min; 28 cycles at 94°C for 1 min, 62°C for
2.5 min, 72°C for 1 min; and 1 cycle at 72°C for 5 min. GAPDH
primers (Clontech) were used as controls for PCR amplification. These
experiments were repeated twice, and similar results were obtained.
PCR fragments were ligated into the pCR2.1-TOPO sequencing plasmid according to the manufacturer’s instructions (Invitrogen, Carlsbad, CA). Plasmid DNA was isolated and subjected to DNA sequencing analysis using the Thermo Sequenase cycle sequencing kit (Amersham Life Science, Cleveland, OH) according to the manufacturer’s instructions. Two plasmids were sequenced from each primer set and showed identical sequence.
Western Blot Analysis.
Breast cancer cells were lysed (30 min, 4°C) in 100 mM
Tris (pH 7.5), 150 mM NaCl, 1% deoxycholate, 1% Triton
X-100, 0.1% SDS, 2 mM phenylmethylsulfonyl fluoride, and 1
mM Pefabloc (Boehringer Mannheim, Indianapolis, IN). Cell
lysates were briefly sonicated and centrifuged, and the total protein
concentration was determined using the bicinchoninic acid protein assay
(Pierce, Rockford, IL). Twenty five µg of protein for each sample
were electrophoresed on a 12.5% polyacrylamide gel under denaturing
conditions, and proteins were transferred onto Immobilon-P membranes
(Millipore, Beford, MA).
Membranes were blocked with Tris-buffered saline containing 5% BSA
(Sigma, St. Louis, MO), and HP1Hs was detected
using a mouse polyclonal HP1Hs-specific
antibody (16)
and a horseradish peroxidase-conjugated goat
antimouse secondary antibody (Amersham Pharmacia, Piscataway, NJ). To
control for the amount of protein loaded per lane, an actin monoclonal
antibody (ICN Biomedicals, Aurora, OH) was used.
HP1Hs and actin proteins were visualized using
the enhanced chemiluminescence detection system according to the
manufacturer’s instructions (Amersham Pharmacia). Each experiment was
repeated at least twice with similar results.
HP1Hs Immunofluorescence.
Breast cancer cell lines (5 x 104
cells/well) were plated onto 12-mm round glass coverslips and grown to
approximately 50% confluence. Cells were fixed in ice-cold methanol
for 5 min. HP1Hs was detected using a mouse
polyclonal HP1Hs-specific antibody
(16)
and a rhodamine-conjugated goat antimouse IgG
secondary antibody (ICN Pharmaceuticals). Coverslips were mounted onto
glass slides for analysis by confocal microscopy using Laser Scanning
Microscope 510 (Carl Zeiss, Inc., Thornwood, NY) with optical
sectioning ranging from 13–27 slices covering a 6–25-µm cell
thickness. These experiments were repeated twice with similar results.
HP1Hs Expression Vector Construction and
Transfection.
The HP1Hs complete coding sequence
was obtained by PCR from MCF-7 cells using a
HP1Hs-specific forward primer
containing an EcoRI restriction site
(5'-GCTCAAGCGAATTCATGGGAAAGAAAACCAAGCGGAC-3') and a
HP1Hs-specific reverse primer containing
BamHI and HindIII restriction sites
(5'-GAGTCCGGAAGCTTTGGATCCCGGCTCTTTGCTGTTTCTTTCTCTTTG-3').
The HP1Hs PCR product was ligated
into the pCR2.1-TOPO TA cloning vector (Invitrogen) and then ligated
into the EcoRI/BamHI restriction sites of the
pEGFP-C2 mammalian expression vector (Clontech), creating a
GFP-HP1Hs fusion protein. The
GFP-HP1Hs construct was
transfected into MDA-MB-231 cells using LipofectAMINE reagent according
to the manufacturer’s instructions (Life Technologies, Inc.).
GFP-HP1Hs-expressing cells were selected in
complete medium containing 400 µg/ml G418.
In Vitro Invasion Analysis.
Analysis of in vitro invasion of breast cancer cell lines
was performed using the MICS assay as described previously
(17)
. The percentage of invasion was calculated as the
total number of invading cells/total number of cells seeded x 100. Each parameter was assayed in triplicate, and each
experiment was repeated twice with similar results.
HP1Hs Immunohistochemistry.
Frozen and formalin-fixed, paraffin-embedded sections of human
benign mammary tissue, primary breast cancer, and metastatic tissues
were obtained from Dr. Ruth Lininger (University of North Carolina,
Chapel Hill, NC). The Vectastain Elite ABC kit (Vector Laboratories,
Burlingame, CA) was used to stain frozen tissue sections according to
the manufacturer’s specifications, except that frozen tissue sections
were quenched with 0.3%
H2O2 in ice-cold methanol
for 5 min at room temperature. Tissue sections were mounted with
Aquamount (Lerner Laboratories, Pittsburgh, PA) for staining analysis.
Formalin-fixed, paraffin-embedded sections of primary and metastatic
breast cancer tissues were deparaffinized, rehydrated in distilled
water, and incubated in 20 mM Tris-HCl buffer (pH 1.5) for
18 h at 60°C. Tissues were washed in distilled water and then
blocked sequentially with avidin, biotin, and serum-free protein block
for 10 min each (LSAB+Alkphos Kit; DAKO, Carpinteria, CA). Tissues were
incubated sequentially with anti-HP1Hs
antibody (16)
, biotinylated linking antibody, and
enzyme-conjugated streptavidin. Sections were stained with Vector red
chromagen (Vector Laboratories) and counterstained with 0.2% light
green stain. Tissues were evaluated for the percentage of cells showing
HP1Hs immunoreactivity and the intensity of
immunoreactivity, which was graded on a scale from 1+ to 3+, with 3+
representing the highest intensity.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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was identified previously among 19
differentially expressed genes whose expression was down-regulated in
an invasive/metastatic breast cancer cell line (MDA-MB-231) compared
with a poorly invasive/nonmetastatic breast cancer cell line (MCF-7;
Ref. 15
). Since these initial studies, we noted that the
MDA-MB-231 cell line had become heterogeneous with respect to cellular
morphology and contained a distinct subpopulation of large,
epithelial-like cells. The density of this subpopulation of large cells
increased with increasing passage of the cell line in culture.
Furthermore, these large epithelial-like cells were positive for
HP1Hs expression, and
HP1Hs mRNA levels in bulk
MDA-MB-231 cell cultures increased over time (data not shown). It is
hypothesized that these large, epithelial-like cells are revertants to
a noninvasive/nonmetastatic
phenotype.5
Therefore, the MDA-MB-231 cell line was enriched for invasive cells by
two rounds of selection through a collagen IV/laminin/gelatin matrix to
establish the MDA-MB-231–2 cell line (Fig. 1A)
. The MDA-MB-231–2 cell line did not contain any large
epithelial-like cells, and HP1Hs
mRNA expression was reduced 34% in the MDA-MB-231-2 cell line compared
with the MCF-7 and T-47D cell lines (Fig. 1B)
. In addition,
HP1Hs protein levels were barely detectable in
MDA-MB-231-2 and Hs578T cells by Western blot analysis (Fig. 1C)
. These results demonstrate a down-regulation of
HP1Hs expression at the mRNA and
protein levels in breast cancer cells with an invasive/metastatic
phenotype.
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or whether it included other
family members, expression of
HP1Hsß and
HP1Hs mRNA in breast cancer cell
lines was also investigated using RT-PCR analysis. As shown in Fig. 1D
, virtually no difference in expression of either
HP1Hsß or
HP1Hs mRNA was observed in the
breast cancer cell lines tested, using GAPDH mRNA levels to normalize
for RNA loading. These results suggest that only the down-regulation of
HP1Hs is associated with the
breast cancer invasive/metastatic phenotype.
Localization of HP1Hs in Breast Cancer Cell Lines.
Breast cancer cell lines were stained with a mouse polyclonal antibody
to human HP1Hs and analyzed by confocal
microscopy to determine HP1Hs expression and
cellular localization patterns. A heavy punctate staining, which was
localized to the nucleus and nuclear membrane, was observed in MCF-7
cells, T-47D cells, and in the poorly invasive subpopulation
(consisting of large epithelial-like cells) within the MDA-MB-231 cell
line before enrichment for more invasive subpopulations (Fig. 2)
. In contrast, a low-level diffuse nuclear staining pattern with little
or no localization in the nuclear membrane was observed in Hs578T,
MDA-MB-231 (in the invasive smaller cells before enrichment for more
invasive subpopulations), and the MDA-MB-231-2 cells (enriched for
highly invasive potential; Fig. 2
). These results corroborate the
reduction in HP1Hs observed in whole cell
lysates and demonstrate changes in HP1Hs
nuclear localization patterns in breast cancer cells with an
invasive/metastatic phenotype.
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Transfection on in
Vitro Invasion. gene downstream to a GFP
gene was constructed (GFP-HP1Hs)
and stably transfected into MDA-MB-231 cells.
GFP-HP1Hs-transfected MDA-MB-231
cells showed GFP fluorescence that localized only to the nucleus,
compared with control GFP-transfected MDA-MB-231 cells that
showed GFP fluorescence predominantly located in the cytoplasm (data
not shown). The ability of control GFP- and
GFP-HP1Hs-transfected MDA-MB-231
cells to degrade and invade a laminin/collagen IV/gelatin-coated
polycarbonate membrane was investigated. As is shown in Fig. 3
, a 43% and 49% reduction in invasion was observed in two
GFP-HP1Hs-transfected MDA-MB-231
clones, compared with control GFP-transfected MDA-MB-231
cells. In addition, analysis of the invasive cells (underside of the
polycarbonate membrane) revealed that approximately 95% were
nonfluorescent (data not shown). These results provide direct evidence
that down-regulation of HP1Hs
expression contributes to breast cancer cell invasion.
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in Human Tissues.
observed in the invasive/metastatic breast cancer cell lines was not
limited to cultured cells, HP1Hs protein
expression was analyzed in clinically relevant tumor tissues. Frozen or
formalin-fixed, paraffin-embedded normal mammary tissue and tissues
from ductal and lobular carcinoma in situ, invasive ductal
carcinoma, and metastatic lesions from distant sites (lymph node, lung,
skin, and omentum) were analyzed for both the percentage of tumor cells
positive for HP1Hs and the intensity of
staining. All of the tumor tissues from nonmetastatic lesions contained
>80% HP1Hs immunoreactive cells with a
staining intensity of up to 3+, as shown in Table 1
. In contrast, seven of nine metastatic tissues from distant sites
contained up to 95% less HP1Hs-positive cells
with a staining intensity of 1–2+ (Table 1)
. Fig. 4
demonstrates HP1Hs nuclear staining of normal
epithelial cells and, to a lesser extent, stromal and myoepithelial
cells in a normal lactating mammary tissue (Fig. 4A)
and
tumor cells in an infiltrating ductal carcinoma (Fig. 4C)
.
In contrast, little or no HP1Hs staining was
observed in the nuclei of tumor cells in lung metastases from two
breast cancer patients (Fig. 4, E and G)
. These
results demonstrate the low level of HP1Hs
protein expression in tumor cells from metastatic lesions.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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One of the proteins known to be involved in chromatin packaging and
gene regulation is HP1, which we identified as being down-regulated in
the invasive/metastatic human breast cancer cell line MDA-MB-231
(15)
. In this study, we observed a down-regulation in
HP1Hs mRNA and protein expression
only in highly invasive/metastatic breast cancer cell lines. This
down-regulation was limited to
HP1Hs expression because
HP1Hsß and
HP1Hs mRNA expression was similar
in all cell lines tested, regardless of invasive/metastatic phenotype,
suggesting that these genes are transcriptionally regulated
differently from HP1Hs. In
addition, we observed that endogenous HP1Hs
expression was greatly increased in MDA-MB-231 cells that have an
epithelial-like morphology (presumably reverted to a noninvasive
phenotype) and that these HP1Hs-positive
epithelial-like cells are poorly invasive in vitro.
Furthermore, MDA-MB-231 cells transfected with
GFP-HP1Hs have a decreased
in vitro invasive potential compared with
GFP-transfected MDA-MB-231 controls. Taken together, these
results support our hypothesis that
HP1Hs expression is capable of
modulating the invasive/metastatic phenotype in breast cancer cells.
Consistent with the data generated from cultured breast cancer cell
lines, clinical pathology findings indicated a reduction in
HP1Hs in tumor cells from seven of nine
distant metastatic lesions from breast cancer patients compared with
normal mammary tissues and primary breast cancer tumors. There are
several possible explanations for why a reduction in
HP1Hs was not observed in tumor cells from one
lung and a lymph node metastatic lesion. The substantial localization
of HP1Hs in the lung tissue of one patient may
be indicative of a tumor lesion that has arrested or reverted to a
nonmetastatic phenotype. This hypothesis might also apply to certain
metastatic lesions in lymph nodes, which may not represent true
metastases. Through localized trauma, cancer cells (whether in
situ or invasive) could be transferred by draining lymph to a
regional lymph node, where they could be trapped and possibly grow.
This could explain the uncommon observation of in situ
carcinoma of the breast associated with lymph node metastasis with no
identifiable invasive tumor (21)
. Additionally, it could
explain why not all patients with lymph node metastases develop distant
metastases and die of their disease. It is also conceivable that not
all mechanisms of metastatic progression in breast cancer cells are
mediated through pathways requiring loss or down-regulation of
HP1Hs expression.
This is the first report that demonstrates an association between a
metastatic phenotype and a reduction in HP1Hs.
We theorize that HP1Hs mediates silencing of
genes involved in the EMT in differentiated normal cells and breast
cancer cells maintaining a nonmetastatic phenotype. Cells that have
undergone EMT have been shown to have a highly invasive/metastatic
phenotype (22
, 23) , concomitant with a down-regulation in
HP1Hs mRNA and protein. In our model of breast
cancer metastatic progression, release of
HP1Hs-mediated silencing would allow an
increase in expression of EMT-related genes and induce the metastatic
phenotype. Whether down-regulation of HP1Hs is
the cause of metastasis-related gene expression or rather a consequence
of other genetic alterations remains to be determined. However, a clear
association between a reduction in HP1Hs and a
breast cancer metastatic phenotype has been shown and may be useful as
a molecular marker in predicting long-term prognosis in breast cancer
patients.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by NIH/National Cancer Institute Grant
CA59702 (to M. J. C. H.), the University of Iowa Carver
Collaborative Award (to D. A. K. and L. L. W.), and The Wellcome
Trust (A. M. A. and W. C. E.). 
2 To whom requests for reprints should be
addressed, at Department of Anatomy and Cell Biology, 1-100 BSB,
University of Iowa, 51 Newton Road, Iowa City, IA 52242-1109. Phone:
(319) 335-7755; Fax: (319) 335-7770; E-mail: dawn-kirschmann{at}uiowa.edu
3 Present address: NIH, National Institute of
Child Health and Human Development, Laboratory of Embryology,
Bethesda, MD 20892.
4 The abbreviations used are: HP1,
heterochromatin-associated protein 1; GFP, green fluorescent protein;
GAPDH, glyceraldehyde-3-phosphate dehydrogenase; RT-PCR, reverse
transcription-PCR; EMT, epithelial to mesenchymal transformation; MICS,
Membrane Invasion Culture System.
5 Dr. Janet Price, personal communication.
Received 3/ 8/00. Accepted 5/18/00.
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K.-K. Hwang, J. C. Eissenberg, and H. J. Worman Transcriptional repression of euchromatic genes by Drosophila heterochromatin protein 1 and histone modifiers PNAS, September 25, 2001; 98(20): 11423 - 11427. [Abstract] [Full Text] [PDF]
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