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Stat5 regulates the phosphatidylinositol 3-kinase/Akt1 pathway during mammary gland development and tumorigenesis.
[cowden syndrome]
Stat
5
(
signal
transducer
and
activator
of
transcription
5
)
is
an
essential
mediator
of
cytokine
receptor
signaling
and
plays
important
roles
in
the
proliferation
of
alveolar
progenitors
and
the
survival
of
functionally
differentiated
epithelial
cells
in
the
mammary
gland
.
A
deregulated
expression
and
activation
of
Stat
5
leads
to
precocious
alveolar
development
in
the
absence
of
pregnancy
hormones
,
impaired
mammary
gland
remodeling
following
the
cessation
of
lactation
,
and
mammary
tumor
formation
.
We
reported
previously
that
Stat
5
induces
the
transcription
of
the
Akt
1
gene
from
a
novel
promoter
.
In
this
report
,
we
provide
experimental
evidence
that
Akt
1
is
an
essential
mediator
for
the
biological
function
of
Stat
5
as
a
survival
factor
.
Additionally
,
Stat
5
controls
the
expression
of
the
regulatory
and
catalytic
subunits
of
the
phosphatidylinositol
3
-
kinase
(
PI
3
K
)
(
p
85
α
and
p
110
α
)
,
thereby
greatly
augmenting
signaling
through
the
prosurvival
PI
3
K
/
Akt
pathway
.
In
agreement
with
this
model
,
we
observed
that
the
constitutive
activation
of
Stat
5
cooperates
with
the
loss
of
function
of
the
tumor
suppressor
PTEN
by
accelerating
the
formation
of
preneoplastic
lesions
and
mammary
tumors
.
The
mammary
gland-
specific
ablation
of
Stat
5
is
sufficient
to
prevent
mammary
carcinogenesis
in
a
genuine
mouse
model
for
Cowden
syndrome
.
Therefore
,
targeting
the
Jak
2
/
Stat
5
pathway
might
be
a
suitable
strategy
to
prevent
breast
cancer
in
patients
that
carry
a
mutant
PTEN
allele
.
