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Cowden syndrome-associated germline SDHD variants alter PTEN nuclear translocation through SRC-induced PTEN oxidation.
[cowden syndrome]
Germline
mutations
in
the
PTEN
tumor
-suppressor
gene
and
germline
variations
in
succinate
dehydrogenase
subunit
D
gene
(
SDHD
-G
12
S
,
SDHD
-H
50
R
)
are
associated
with
a
subset
of
Cowden
syndrome
and
Cowden
syndrome
-like
individuals
(
CS
/
CSL
)
and
confer
high
risk
of
breast
,
thyroid
and
other
cancers
.
However
,
very
little
is
known
about
the
underlying
crosstalk
between
SDHD
and
PTEN
in
CS
-associated
thyroid
cancer
.
Here
,
we
show
SDHD
-G
12
S
and
SDHD
-H
50
R
lead
to
impaired
PTEN
function
through
alteration
of
its
subcellular
localization
accompanied
by
resistance
to
apoptosis
and
induction
of
migration
in
both
papillary
and
follicular
thyroid
carcinoma
cell
lines
.
Other
studies
have
shown
elevated
proto-oncogene
tyrosine
kinase
(
SRC
)
activity
in
invasive
thyroid
cancer
cells
;
so
,
we
explore
bosutinib
,
a
specific
inhibitor
for
SRC
,
to
explore
SRC
as
a
mediator
of
SDH-
PTEN
crosstalk
in
this
context
.
We
show
that
SRC
inhibition
could
rescue
SDHD
dysfunction-induced
cellular
phenotype
and
tumorigenesis
only
when
wild-
type
PTEN
is
expressed
,
in
thyroid
cancer
lines
.
Patient
lymphoblast
cells
carrying
either
SDHD
-G
12
S
or
SDHD
-H
50
R
also
show
increased
nuclear
PTEN
and
more
oxidized
PTEN
after
hydrogen
peroxide
treatment
.
Like
in
thyroid
cells
,
bosutinib
decreases
oxidative
PTEN
in
patient
lymphoblast
cells
carrying
SDHD
variants
,
but
not
in
patients
carrying
both
SDHD
variants
and
PTEN
truncating
mutations
.
In
summary
,
our
data
suggest
a
novel
mechanism
whereby
SDHD
germline
variants
SDHD
-G
12
S
or
SDHD
-H
50
R
induce
thyroid
tumorigenesis
mediated
by
PTEN
accumulation
in
the
nucleus
and
may
shed
light
on
potential
treatment
with
SRC
inhibitors
like
bosutinib
in
PTEN
-wild-
type
SDHD
-variant
/
mutation
positive
CS
/
CSL
patients
and
sporadic
thyroid
neoplasias
.
Diseases
Validation
Diseases presenting
"high risk"
symptom
22q11.2 deletion syndrome
acute rheumatic fever
adrenal incidentaloma
alpha-thalassemia
aniridia
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cowden syndrome
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cutaneous mastocytosis
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esophageal carcinoma
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phenylketonuria
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werner syndrome
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