May 2024 SOCRA Source Journal - Journal - Page 50
has been carried out on STAT1,
a great many unanswered
questions remain. Most studies
were concerned with the action
of single extracellular signaling
polypeptides, but cells in tissues
are often exposed to multiple
agents simultaneously, such as,
increased cAMP can blunt the
activation of the STAT1 family,
and prior treatment of cells
with granulocyte-macrophage
colony-stimulating factor (GMCSF) can prevent 1L-6 induced
activation of STAT1. Additionally,
it still remains unknown how
STAT1-dependent transcriptional
initiation is regulated (Darnell
1997).
10. The Role of STAT1 in
Breast Cancer
Based on the evidence currently
available, a large body of studies
show correlated tumour–upregulation of STAT1 with late
stage of breast cancer. In the
past, work of the Brown group
(2007) had demonstrated
increased tumour STAT1
immunostaining especially at
the tumour stromal borders in
human breast tumour specimens,
when compared with normal
breast tissue. Additionally, he
found invasive carcinoma biopsy
samples from human breast
tumour sections show increased
phospho-STAT1.
STAT1 protein expression levels
and they showed that STAT1
activates anti-proliferative and
pro-apoptotic genes, which
has been classically associated
with anti-viral and anti-tumour
immunity. In addition, loss of
STAT1 is associated with breast
cancer development based on
data using STAT1-/- models.
However, it is essential to
mention that the immune system
in wild type mice does not
function exactly the same as that
in STAT-/-model. Based on these
studies, STAT1 over–expression
in breast cancer may have a
tumour-suppression role (Hix et
al. 2013).
Existing research recognizes the
critical role played by STAT1
on the immune system as a
regulatory factor to the group
of genes involved in promoting
chronic in昀氀ammatory disease,
and inhibiting STAT1 signaling
for the treatment of autoimmune
disease is an active area of
research. Both isoform (α and
β) are highly expressed when
the IFN-signaling pathway is
activated and are associated
with a tumour suppressor and
pro-apoptotic function in some
experimental systems (Khodarev
et al. 2004).
The immunostaining method
observed signi昀椀cant staining and
provided conclusive evidence
that increased tumour STAT1
activation is proportional to an
increase of disease progression
in human breast cancer (Hix et al.
2013). Throughout this literature,
new evidence reveals that STAT1
overexpression in breast cancer
might have a tumour promoting
rather than a tumour suppressor
role (Kovacic et al. 2006, Perou
et al. 1999).
In addition, this author demonstrated in human breast cancer
biopsies that tumour cell
expression of constitutively
active STAT1 correlates with
increasing disease progression
from DCIS to invasive carcinoma.
The question is what is the
mechanism by which STAT1
promotes tumour progression in
an immunocompetent model?
Various methods have been
developed and introduced to
measure STAT1 and to study its
potential role in the regulation
of DNA repair pathway genes
and regulation of numerous
pro-in昀氀ammatory cytokines and
chemokines. Acute in昀氀ammation
is highly bene昀椀cial for antitumour immunity. On the other
hand, chronic in昀氀ammation
is an established driver of
tumourigenesis and is highly
correlated with metastatic tumour
progression (Hix et al. 2013).
The more surprising correlation
is with STAT1 signaling,
which is implicated in several
in昀氀ammation-driven diseases
such as rheumatoid arthritis
(de Prati et al. 2005).
STAT1 over–expression has been
demonstrated in several human
cancers, including head and neck
cancer (Buettner et al. 2002) and
breast cancer (Greenwood et al.
2012). In terms of cancer, STAT1
has been associated with an
anti-tumour effect; however, the
large accumulation of evidence
has linked increased STAT1
activation with increased tumour
progression in multiple types
of cancer, for example, breast
cancer (Hix et al. 2013).
50
Several studies in multiple
cancer models have implicated
constitutive STAT1 activation
as tumour promoting, for
example, the high level of STAT1
expression in human squamous
carcinoma cells was found to
induce pro-survival genes and
resistance to genotoxic stress.
The Ming Zhang group (2013)
has used mouse carcinoma
cell lines and mouse models
to study the mechanism of
STAT1 modulation on tumour
progression. This group has
been studying these models
which were created with varying
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