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6ß4 Integrin-Mediated Invasive Phenotype1
Department of Clinical Physiopathology (L.B., M.M., G.F., E.B.), Andrology Unit (M.S.), Internal Medicine (V.C.) and Urology (M.C.), University of Florence, viale Pieraccini 6, I-50139 Florence, Italy; U.O. Anatomia Patologica Ospedale S. Maria Annunziata (A.S., A.G.), I-50139 Florence, Italy
Address all correspondence and requests for reprints to: Elisabetta Baldi, Department of Clinical Physiopathology, Andrology Unit, University of Florence, viale Pieraccini, 6, I-50139, Florence, Italy. E-mail: e.baldi{at}dfc.unifi.it
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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6ß4 integrin
expression may be one of the molecular mechanisms responsible of this
phenomenon. We found that protein and gene expressions of 6 and ß4
subunits were strongly reduced in the androgen-sensitive cell line
LNCaP respect to the androgen-independent PC3 and that transfection of
PC3 cells with a full-length androgen receptor expression vector
resulted in a decreased expression of 6ß4 integrin, reduced
adhesion on laminin, and suppressed Matrigel invasion. Growth in soft
agar was also suppressed in androgen receptor-positive PC3 clones.
Treatment of androgen receptor positive clones with the synthetic
androgen R1881 further reduced 6 and ß4 messenger RNA expression
as well as adhesion on laminin and Matrigel invasion. Our results
indicate that androgens regulate cell-extracellular matrix adhesion and
invasion by modulation of integrin expression and function, thus
keeping a low invasive phenotype of prostate cancer cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ß subunits (9). In the last few
years, compelling evidence emerged on the role of integrins in the
regulation of proliferation and invasion of carcinomas (10). In
particular, the integrin 6ß4, one of the receptor for laminins,
has been shown to play a pivotal role in migration and invasion of
carcinoma cells (11, 12, 13, 14). Indeed, while in epithelia, 6ß4 mediates
the formation of stable adhesive structures termed hemidesmosomes (15)
that link intermediate filaments with extracellular matrix, in
carcinoma cells, this integrin promotes the migration on laminin
through association with actin cytoskeleton (11). Few studies have been
performed so far on 6ß4 integrin expression in prostate carcinoma
cells (16, 17, 18, 19).
In this study, we investigated whether androgens are involved in the
regulation of the expression and function of 6ß4 integrin in human
prostate carcinoma cells. The effects of androgen on integrin
expression and cell adhesion properties were studied in the
androgen-sensitive carcinoma cell line LNCaP and in the
androgen-independent PC3 cells transfected with a full-length human
androgen receptor complementary DNA (cDNA). Our data demonstrate that
expression of androgen receptor in transfected PC3 cells results in
decreased levels of 6ß4, providing a possible explanation for the
lower malignant phenotype (lower invasion and anchorage-independent
growth) observed in the cell line after transfection.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2 and 3 were obtained
from Life Technologies, Inc. (Gaithersburg, MD). Rat mAb
anti-6 (GoH3) was from Immunotech (Marseille, France).
Mouse mAb UM-A9 (anti ß4) was kindly provided by Dr. T. E. Carey
(University of Michigan, Ann Arbor, MI) and rat mAb AIIB2 (anti ß1)
by Dr. C. Damski (University of California, San Francisco, CA).
Matrigel was from Collaborative Biomedical Products (Bedford, MA), and
type I collagen was provided by Dr. D. Schuppan (Free University,
Berlin, Germany). The antibiotic G418 (Geneticin) was obtained from
Calbiochem (La Jolla, CA). Other reagents not
specified were from Sigma (St. Louis, MO).
Cell culture and transfection
Cell lines (LNCaP, DU145, and PC3) were obtained from American
Type Culture Collection (Manassas, VA) and maintained
respectively in RPMI, DMEM, and HAM-F12 Coon supplemented with 10%
FBS, 1% penicillin/streptomycin, and 1% glutamine. Before stimulation
with androgens, cells were kept for 24 h in serum- and phenol
red-free medium. PC3 cells were transfected with human full-length
androgen receptor construct (p5HbhAR) or vector alone (PC3-NEO cells)
by electroporation method using 10 µg of plasmid DNA. Cells were then
selected in the presence of 0.5 mg/ml geneticin (G418,
Calbiochem). To obtain stable colonies, individual clones
were isolated by limiting dilution and tested for the presence of the
androgen receptor both by Northern and Western analysis.
Flow cytometry analysis
Flow cytometry was performed as described (20). Cells were grown
on Petri dish until confluence, washed with PBS, detached with 0.1%
trypsin-EDTA, and resuspended in PBS supplemented with 1 mM
CaCl2, 1 mM
MgCl2. Cells were then incubated for 30 min at 4
C with the different antiintegrin antibodies, or nonspecific IgG as
control, washed three times with PBS and further incubated with
FITC-conjugated goat antimouse or antirat secondary antibody (1:200)
for 30 min. After washing three times, cells were fixed with 3%
paraformaldehyde in PBS and analyzed by FACScan/Lysys II software
(Becton Dickinson and Co., Mountain View, CA).
Northern blot analysis
RNA extraction and Northern blotting were performed as reported
previously (21). Briefly, total cell RNA was prepared by hot phenol
method, 20 µg were then fractionated in 1% agarose-formaldehyde gel
and transferred overnight onto nylon membranes. After prehybridization
for 1 h, membranes were hybridized with 3.3-kb 6
HindIII cut cDNA, or 2.98-kb ß1 EcoRI cut cDNA,
or 5.5-kb ß4 EcoRI cut cDNA radiolabeled with
[-32P]dCTP by random priming. The membranes
were then washed three times and submitted to autoradiography using
Kodak X-Omat AR films and Kodak X-Omatic
regular intensifying screen at -80 C.
Mitogenic assays
[3H]thymidine (NEN Life Science Products, Boston MA), incorporation was evaluated as
described previously (21). Briefly, cells were plated in 24-well plates
in complete culture medium. After 2 days of culture, cells were kept in
serum- and phenol red-free medium for 24 h before treatments.
Cells were then treated with R1881 (0.1 and 1 nM) in phenol
red- and serum-free medium for the indicated times.
For experiments on the effect of R1881 on cell number, cells were plated at low density in 6-well plates, treated exactly as for [3H]thymidine incorporation assay, and counted with a Coulter Counter (Coulter Electronics, Ltd., Luton, UK) after trypsinization.
Western blot analysis
Protein extraction and Western blot analysis were performed as
previously described (22). Briefly, cells were scraped in PBS
supplemented with 1 mM
Na3VO4 centrifuged, and
resuspended in lysis buffer (20 mM Tris, pH 7.4, 150
mM NaCl, 0.25% NP-40, 1 mM
Na3VO4, 1 mM
PMSF). After measurement of proteins, cell extracts were diluted in
Laemmli sample buffer, boiled at 90 C for 5 min and loaded on 8%
polyacrylamide-bisacrylamide gels. Proteins were transferred to
nitrocellulose membrane and incubated with antiandrogen receptor
antibody (1:1000 dilution) for 1 h, washed, and incubated with
secondary antibody (peroxidase-conjugated antirabbit antiserum, 1:4000)
for 1 h. After washing, the blots were incubated with enhanced
chemiluminescence (ECL, Amersham Pharmacia Biotech)
detection reagent and exposed to film.
Adhesion assay
Adhesion assays were performed as described previously (20).
Briefly, flat 96-multiwell plates were coated with 100 µg/ml
poly-lysine for 10 min at 37 C or with 10 µg/ml laminin-1 or 10
µg/ml type-I collagen or 20 µg/ml fibronectin overnight at 4 C in
PBS. After washing with PBS, 105 cells/well were
added in triplicate and incubated for the indicated times. Wells were
then washed three times with PBS, and cells were fixed in formaldehyde
for 10 min and stained with 0.5% solution of crystal violet. Adhesion
was quantitated by measuring the absorbance at 600 nm. The values are
reported as the percent of poly-L-lysine (considered as
100% of cellular adhesion).
Invasion assay
Invasion assays were performed as described previously (20)
according to Albini et al. (23) using the Boyden chambers
equipped with 8 µm porosity polyvinylpyrrolidone-free polycarbonate
filters. A thin layer of Matrigel solution (50 µg/ml) was overlaid on
the upper surface of the filter and allowed to gel by incubating the
filters at 37 C for 30 min. Cell ability to invade the substrate was
assessed by using epidermal growth factor (EGF). EGF (100 ng/ml in
DMEM) was added to the bottom well of the Boyden chambers.
105 cells were added to the top of the chambers
and incubated for 24 h at 37 C. Migrated cells were quantitated by
counting cells with a Carl Zeiss microscope (Oberkochen,
Germany) equipped with brightfield optics (40x magnification). Results
are expressed as the number of migrated cells per high-power field.
Anchorage-independent growth assay
Anchorage-independent growth was determined as the ability of
the cells to form colonies in soft agar (20). Cells were suspended in 2
ml of 0.3% select agar in medium containing 20% charcoal-treated FBS
in presence or absence of 1 nM R1881, and plated into
six-well plates. After 15 days, growth was examined with an inverted
microscope and individual colonies (10 cells or more) were blindly
counted by two different investigators.
Statistical analysis
Statistical analysis was performed by paired (when applicable)
and unpaired Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2ß1, 3ß1, 6ß1, and 6ß4. Surface
expression of 2, 3, 6, ß1, and ß4 integrin subunits was
determined in two human prostate carcinoma cell lines by flow
cytometric analysis: the androgen-sensitive LNCaP and the
androgen-independent PC3, characterized respectively by absent and high
ability to develop tumor in SCID mice (16). As shown in Fig. 1
, LNCaP cells expressed little or none
surface 2, 3, 6, and ß4 integrins compared with PC3, whereas
ß1 expression was similar in the two cell lines, confirming previous
results (16, 18, 19). Northern blot analysis of messenger RNA (mRNA)
expression for 6, ß4, and ß1 in the two cell lines confirmed the
results of flow cytometric analysis. The highest mRNA levels of 6
and ß4 integrin subunits were found in PC3 cells, whereas LNCaP
showed low (6) or undetectable (ß4) transcripts of the two
integrins (Fig. 2). Conversely, ß1 mRNA
levels were similar in the two cell lines (Fig. 2). Because LNCaP cells
retain androgen sensitivity, we examined whether treatment of these
cells with DHT affected mRNA expression of 6, ß4, and ß1
integrin subunits. mRNA expression for 6 was reduced by treatment
with 0.1 nM DHT (D, Fig. 2), whereas no effects were
observed on ß1 mRNA. Similarly, ß4 mRNA levels remained
undetectable also after treatment with DHT (Fig. 2). These data
indicate a possible regulation of 6 gene expression by androgens in
LNCaP cells. As expected, no effects of DHT were observed in PC3 cells
(Fig. 2). Similar results were obtained with the synthetic androgen
R1881 (not shown).
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, adhesion on laminin (panel A) and on
collagen (panel B) of LNCaP cells was significantly lower at all time
points compared with PC3. Conversely, adhesion on fibronectin did not
differ between LNCaP and PC3 cell lines (Fig. 3C). In keeping with
their reduced tumurogenicity (16), LNCaP cells were also characterized
by reduced ability to form colonies in soft agar respect to PC3 cells
(data not shown).
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6ß4 integrin expression and adhesion properties of PC3
cells transfected with an androgen receptor expression vector6 and ß4
integrin subunits, could represent a suitable in vitro model
to study regulation of these integrins by androgens. After selection
and cloning of PC3 transfected cells, we evaluated the presence of
androgen receptor by both Northern blot (not shown) and Western blot
analysis (Fig. 4). Several positive
clones, showing a protein band of 110 kDa exactly migrating as the
androgen receptor from LNCaP cells, were obtained. The protein band was
absent (Fig. 4) in androgen-receptor negative cell lines PC3WT, PC3
Mock-transfected (PC3-Neo) and DU145 (16). In some clones, the level of
androgen receptor expression was lower than in LNCaP cells, whereas in
clones 6 and 13 a similar level of expression was observed (Fig. 4), and thus further studies were conducted in these two clones.
Because loss of the transcript may occur in stable transfected cells,
androgen receptor expression in positive clones was frequently checked
by Western blot analysis. To ascertain whether the androgen receptor in
clone 6 and 13 cells was functional, we evaluated the effect of R1881
(0.1 and 1 nM for 6 days) on
[3H]thymidine incorporation. As shown in Fig. 5, 1
nM R1881
determined a significant decrease of
[3H]thymidine incorporation in the two clones,
whereas no effects were observed in PC3-Neo cells. Accordingly, number
of cells was also decreased in the two clones, but not in PC3-Neo
cells, by treatment with 1 nM R1881 (not shown).
At 0.1 nM, a significant effect of R1881 was
observed only in clone 13 cells (Fig. 5). As shown in Fig. 5, the
effects of R1881 were antagonized by the androgen receptor antagonist
bicalutamide in both clones, indicating that the effects on cell growth
of the synthetic androgen are mediated by binding to the androgen
receptor. These results are in agreement with previous findings on the
effect of androgen on growth of androgen receptor transfected PC3-cells
(24, 25).
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6ß4, we measured mRNA
expression and surface distribution of the integrin in androgen
receptor positive clones in basal conditions and after treatment with
R1881 (1 nM, 3 days). As shown in Fig. 6, basal (lanes marked as C) 6 and
ß4 mRNA expression was reduced in clones 6 and 13 with respect to
PC3-Neo or PC3-WT cells. In addition, mRNA expression for both integrin
subunits was further reduced in the two clones by treatment with 1
nM R1881 for 3 days (Fig. 6 lanes marked as T).
Densitometric analysis of mRNA bands in the film performed by Image
quest IQ Base software (Hamamatsu Photonics, Tokyo, Japan) as
previously described (22), revealed that basal mRNA for 6 in clone 6
and 13 was, respectively, 46 ± 14.4% and 52.6 ± 13.5%,
whereas for ß4 was 42 ± 26.5% and 59 ± 17% respect to
PC3-Neo (n = 3 experiments). Conversely, ß1 mRNA expression in
androgen receptor positive clones was similar to PC3-Neo cells and was
unaffected by treatment with R1881 (not shown). In agreement with these
results, surface expression of 6 and ß4 subunits, analyzed by
FACScan, was lower in clones 6 and 13 compared with PC3-Neo cells,
whereas ß1 expression remained unchanged (Fig. 7). In addition, the two clones were
distinguished from PC3-Neo cells by the presence of a cell population
expressing 6 and ß4 at the same levels of negative histograms
(Fig. 7). Based on the relative mean fluorescence intensity, the
percent decrease respect to PC3-Neo cells for 6 and ß4 expressions
were respectively of 63 ± 15 and 55 ± 12 for clone 6 and
35 ± 9 and 53 ± 18 for clone 13 (mean ±
SEM, n = 3). Despite the reduction of mRNA expression
of both 6 and ß4 after treatment with R1881 (Fig. 6), no
substantial quantitative modifications were observed on surface protein
expression of the two integrins, evaluated by FACScan, in both
an-drogen-positive clones (not shown). Similar results were
obtained also in LNCaP cells, where the inhibitory effect of androgens
on mRNA expression of 6 integrin (Fig. 2) did not result in changes
in surface protein expression as analyzed by FACScan (not shown).
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), whereas
adhesion on collagen was similar in the three cell lines (Fig. 8B).
Treatment with R1881 (1 nM, 3 days) further reduced
adhesion to laminin at 15 min of clone 6 and 13, whereas that of
PC3-Neo cells was unaffected (Fig. 8C). A similar reduction of adhesion
to laminin was observed in LNCaP cells after treatment with R1881
(Fig. 8C).
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, clone 6 and 13 cells invaded
significantly less respect to PC3-Neo cells both in basal conditions
and after treatment with EGF (100 ng/ml). Invasion of clone 6 and 13
cells was further reduced significantly by treatment with 1
nM R1881 for 3 days. No invasion was observed in
LNCaP cells either in basal conditions or following treatment with
R1881 (Fig. 9).
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), indicating that restoration of
androgen sensitivity and decreased expression of 6ß4 result also
in a lower anchorage-independent growth. The presence of 1
nM R1881 in the medium determined a further decrease in the
number of colonies that, however, was statistically significant in
clone 6 but not in clone 13 cells (Fig. 10).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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6ß4 integrin expression and function. We demonstrate
that restoration of androgen sensitivity in a androgen-independent
prostrate carcinoma cell line suppresses 6ß4-mediated invasion by
modulating the expression of this integrin.
The invasive phenotype requires specific quantitative and qualitative
expression, on the cell surface, of various molecules that participate
in the interaction between cancer cells and extracellular matrix. In
the case of prostate carcinomas, highly invasive tumors develop after
some time of androgen-ablation therapy probably due to selection of
clones that have bypassed hormone dependency for proliferation and
progression (3), suggesting that androgen may have specific modulating
effects on molecules that regulate the invasive phenotype. Along this
line, it has been recently demonstrated that androgens regulate neutral
endopeptidase (NEP), which is not expressed in cells lines lacking
androgen receptor such as PC3 and DU145 and is highly expressed in
LNCaP (3). Our study documents that loss of androgen regulation may
result in increased 6ß4 integrin expression and consequent more
aggressive, metastatic phenotype. Indeed, 6ß4 expression is high
in the androgen-independent prostatic cancer cell line PC3 and is
barely detectable in LNCaP cells that retain androgen sensitivity,
suggesting a relation between androgen sensitivity and expression of
the integrin. In addition, we demonstrate that expression of the
integrin is strongly decreased in PC3 clones regaining androgen
sensitivity after transfection with an androgen receptor expression
vector. Of importance, androgen receptor transfected-PC3 as well as
LNCaP cells exhibit lower invasion on Matrigel and adhesion to laminin,
indicating that expression of this receptor affects these two
processes. In particular, the lower invasion ability demonstrated by
these cells indicates that expression of the androgen-receptor is
associated to a lower invasive potential. Our study clearly indicates
that such effects of the androgen receptor are due to modulation of
6ß4 expression. Indeed, decreased response to EGF does not appear
to be responsible for the lower invasion observed in our study because
it has been shown that expression of EGF receptor and affinity for its
ligand are actually increased in PC3 cells transfected with the
androgen receptor (26). Similarly, the presence of EGF receptors has
been shown in LNCaP cells (27), which, in our hands, were not able to
invade Matrigel. In addition, preliminary data obtained in our
laboratory indicate that thymidine incorporation in response to EGF
increased similarly both in PC3 transfectants and LNCaP cells (results
not shown). Hence, decreased (PC3 transfectants) or absent (LNCaP
cells) expression of 6ß4 are likely responsible for the lower
invasion. These results confirm and extend previous findings indicating
a major role for this integrin in invasion and progression of cancer
cells (11, 12, 13, 14, 28, 29). Expression of androgen receptor also abrogated
anchorage-independent growth of PC3 transfectants, suggesting that
6ß4 expression is critical to maintaining the transformed
phenotype of these cells. A role for integrins in anchorage-independent
growth of cancer cells has been already suggested (30, 31). In
particular, it has been recently shown that knockout of 6ß1 in
hepatocarcinoma cells by transfection with a ß4 deleted subunit
resulted in a decrease of colony formation in soft agar (20), and
function blocking ß1 antibodies abrogated colony formation of breast
cancer cells in a 3-dimensional basement membrane (32). It is of
interest that the decrease of expression of 6ß4 integrin in PC3
transfectants is obtained without stimulation of the androgen-receptor.
It is possible that androgen present in serum (10% FBS) contained in
the culture medium is sufficient to stimulate the androgen receptor in
the cells. Alternatively and in addition, other factors present in
serum may act as stimuli for the androgen receptor. In this respect, it
has been demonstrated that steroid receptor in general (33) and
androgen receptor in particular may be activated by nonsteroidal
molecules such as interleukin 6 (34), insulin-like growth factor I,
keratinocyte growth factor, and epidermal growth factor (35, 36).
Stimulation of transfected PC3 cells and LNCaP cells with the synthetic
androgen analog R1881 determined a further decrease of 6ß4 mRNA
expression, adhesion on laminin, and invasion, indicating that the
androgen may have direct effect in the regulation of the invasive
phenotype of these cells. However, despite the effects on steady-state
mRNA levels and function of the integrin, by FACScan analysis, we were
unable to demonstrate any significant effect of treatment with R1881 on
surface expression of 6 and ß4 subunits in androgen receptor
transfected PC3 cells. The reason for this discrepancy is unknown and
is at present under investigation in our lab. One possible explanation
is that stimulation with androgens leads to functional modifications of
6ß4 also through posttranscriptional regulation as it has been
shown for the androgen receptor in LNCaP cells (37, 38). In these
cells, androgens induce a decrease of mRNA expression and function of
androgen receptor without observed quantitative alterations (37) or
even an increase (38) of protein expression. Moreover, a possible
interference of androgens with the signal transduction mechanisms of
6ß4 determining a functional alteration of its affinity state
cannot be excluded. Suppression of integrin activation through
modulation of affinity state by ras/MAPK pathway has been demonstrated
(39). Such a pathway may be activated by the androgen receptor (40). On
the other hand, it has been recently shown that retinoids inhibit
adhesion to laminin of human pancreatic carcinoma cells by interfering
with 6ß1 function without altering surface expression of the
integrin (41) and that effects of dexamethasone on adhesion to laminin
of human melanoma cell lines occur without alterations of laminin
receptor expression (42), indicating a possible interference of
molecules with steroid configuration with the signal transduction
pathways and/or affinity state of the integrin.
A steroid receptor binding homologue is present in the human 6
gene promoter (43, 44), suggesting that the protein can be regulated by
steroids. However, this element does not appear to be required for
basal promoter activity (44). Other possible regulatory elements of
6 gene promoter are represented by Sp1, AP2, Ker1, NF-kB, and
c-myc binding elements, located upstream of the
transcription start site (43, 44). Cell-type specific negative
regulatory elements, not yet identified, have been hypothesized in the
upstream region of the promoter (43, 44). The promoter of ß4 has been
characterized recently (45). Gel retardation assays and mutational
analysis have disclosed that a cooperation between AP1 and Ets
regulates the promoter activity of ß4 (45). It has been shown that
androgen receptor-mediated negative regulation of gene expression
occurs mainly by physical interaction of the androgen receptor with Ets
proteins (40), and most of the genes that are transcriptionally
down-regulated by the androgen receptor have Ets binding sites in their
promoter region (40). Interactions of the androgen receptor with
AP-1/c-Jun (46) and NF-kB (40) have been also demonstrated.
In this light, it is conceivable that interaction of the androgen
receptor with 6 or ß4 transcription factors might represent a
pathway of regulation of these genes. It has been recently reported
that expression of 6 and ß4 in several human breast cancer cell
lines is inversely related to the expression of the estrogen receptor
in the same cells (47). This report, together with results described in
the present study, strongly suggests a role for steroid receptors in
the modulation of 6ß4 integrin.
In conclusion, we show consistent evidence that adhesion and invasion
of prostate carcinoma cells is suppressed by expression of androgen
receptor through regulation of 6ß4 integrin expression. These
results imply that androgens have negative effects on genes involved in
the development of invasive phenotype of this tumor and that
antagonistic hormonal treatment may have significant clinical
implications because androgen withdrawal may result in 6ß4
up-regulation and higher invasive phenotype.
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Acknowledgments |
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Footnotes |
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Received January 7, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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6ß4 functions in carcinoma cell migration on laminin-1 by
mediating the formation and stabilization of actin-containing motility
structures. J Cell Biol 139:1873–18846ß4 in the invasive properties of
colorectal carcinoma cells. Cancer Res 56:4811–48196ß4
integrin promotes carcinoma invasion. Cell 91:949–960[CrossRef][Medline]
6ß1 and 6ß4 integrins in human prostate cancer progression.
Cancer Metastasis Rev 14:219–228[CrossRef][Medline]
6ß1-integrin
expression reverses the transformed phenotype of hepatocarcinoma cells.
Gastroenterology 115:433–442[CrossRef][Medline]
in human prostate cancer cells. Br J Cancer 80:657–669[CrossRef][Medline]
6 integrin is associated
with malignant conversion in mouse skin tumorigenesis. Proc Natl Acad
Sci USA 92:7041–70456ß1-integrin receptor.
Gastroenterology 112:532–542[CrossRef][Medline]
6
integrin subunit gene. Biochem Biophys Res Commun 241:258–263[CrossRef][Medline]
6 integrin gene promoter. DNA Cell Biol 16:929–937[Medline]
6 integrins are associated with the metastatic
phenotype of human breast cancer cells. Clin Exp Metastasis 17:325–332[Medline]
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L. G. Sheflin, W. Zhang, and S. W. Spaulding Androgen Regulates the Level and Subcellular Distribution of the AU-Rich Ribonucleic Acid-Binding Protein HuR Both in Vitroand in Vivo Endocrinology, June 1, 2001; 142(6): 2361 - 2368. [Abstract] [Full Text] [PDF]
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