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Upregulated WAVE3 expression is essential for TGF-β-mediated EMT and metastasis of triple-negative breast cancer cells.
[wiskott-aldrich syndrome]
Breast
cancer
is
the
second
leading
cause
of
cancer
death
in
women
in
the
United
States
.
Metastasis
accounts
for
the
death
of
~
90
%
of
these
patients
,
yet
the
mechanisms
underlying
this
event
remain
poorly
defined
.
WAVE
3
belongs
to
the
WASP
/
WAVE
family
of
actin-binding
proteins
that
play
essential
roles
in
regulating
cell
morphology
,
actin
polymerization
,
cytoskeleton
remodeling
,
cell
motility
,
and
invasion
.
Accordingly
,
we
demonstrated
previously
that
WAVE
3
promotes
the
acquisition
of
invasive
and
metastatic
phenotypes
by
human
breast
cancers
.
Herein
,
we
show
that
transforming
growth
factor
-β
(
TGF-β
)
selectively
and
robustly
induced
the
expression
of
WAVE
3
in
metastatic
breast
cancer
cells
,
but
not
in
their
nonmetastatic
counterparts
.
Moreover
,
the
induction
of
WAVE
3
expression
in
human
and
mouse
triple-negative
breast
cancer
cells
(
TNBCs
)
by
TGF-β
likely
reflects
its
coupling
to
microRNA
expression
via
a
Smad
2
-
and
β
3
integrin-dependent
mechanism
.
We
further
demonstrate
the
requirement
for
WAVE
3
expression
in
mediating
the
initiation
of
epithelial-mesenchymal
transition
(
EMT
)
programs
stimulated
by
TGF-β
.
Indeed
,
stable
depletion
of
WAVE
3
expression
in
human
TNBC
cells
prevented
TGF-β
from
inducing
EMT
programs
and
from
stimulating
the
proliferation
,
migration
,
and
the
formation
of
lamellipodia
in
metastatic
TNBC
cells
.
Lastly
,
we
observed
WAVE
3
deficiency
to
abrogate
the
outgrowth
of
TNBC
cell
organoids
in
3
-
dimensional
organotypic
cultures
as
well
as
to
decrease
the
growth
and
metastasis
of
4
T
1
tumors
produced
in
syngeneic
Balb
/
C
mice
.
Indeed
,
WAVE
3
deficiency
significantly
reduced
the
presence
of
sarcomatoid
morphologies
indicative
of
EMT
phenotypes
in
pulmonary
TNBC
tumors
as
compared
to
those
detected
in
their
parental
counterparts
.
Collectively
,
these
findings
indicate
the
necessity
for
WAVE
3
expression
and
activity
during
EMT
programs
stimulated
by
TGF-β
;
they
also
suggest
that
measures
capable
of
inactivating
WAVE
3
may
play
a
role
in
alleviating
metastasis
stimulated
by
TGF-β
.
Diseases
Validation
Diseases presenting
"breast cancers"
symptom
wiskott-aldrich syndrome
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