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مجال
التميز
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تميز دراسي وبحثي
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البحوث المنشورة
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البحث (1):
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عنوان البحث:
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Activation of the Farnesoid X-receptor in
breast cancer cell lines results in cytotoxicity but not increased migration
potential
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رابط إلى البحث:
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here
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تاريخ النشر:
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03/11/2015
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موجز عن البحث:
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Breast cancer is the
commonest form of cancer in women, but successful treatment is confounded by
the heterogeneous nature of breast tumours: Effective treatments exist for
hormone-sensitive tumours, but triple-negative breast cancer results in poor
survival. An area of increasing interest is metabolic reprogramming, whereby
drug-induced alterations in the metabolic landscape of a tumour slow tumour
growth and/or increase sensitivity to existing therapeutics. Nuclear receptors
are transcription factors central to the expression of metabolic and transport
proteins, and thus represent potential targets for metabolic reprogramming. We
show that activation of the nuclear receptor FXR, either by its endogenous
ligand CDCA or the synthetic GW4064, leads to cell death in four breast cancer
cell lines with distinct phenotypes: MCF-10A (normal), MCF-7 (receptor
positive), MDA-MB-231 and MDA-MB-468 (triple negative). Furthermore, we show
that the mechanism of cell death is predominantly through the intrinsic
apoptotic pathway. Finally, we demonstrate that FXR agonists do not stimulate
migration in breast cancer cell lines, an important potential adverse effect.
Together, our data support the continued examination of FXR agonists as a novel
class of therapeutics for the treatment of breast cancer.
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المؤتمرات العلمية:
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المؤتمر (1):
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عنوان المؤتمر:
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8th Saudi Students Conference
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تاريخ الإنعقاد:
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31/01-01/02/2015
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مكان
الإنعقاد:
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London, UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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Farnesoid X
Receptor role on modulation of Matrix Metalloproteinases -2 and -9 in
Metastatic Breast Cancer
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ملخص المشاركة:
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Advanced breast
carcinoma is a main cause of mortality affecting women. It is associated with
poor prognosis; therefore, understanding the molecular mechanisms of invasive
malignancies is critical in order to discover new therapies. The aim of the
current study was to investigate whether Farnesoid X receptor (FXR); a
nuclear receptor which is highly expressed in Breast carcinoma is a novel
regulator of matrix metalloprotease-2 and -9 (MMP-2 and-9) that play main
role in breast cancer metastasis, and their endogenous inhibitors, Tissue
inhibitors of metalloproteases (TIMPs). TIMP-2 and-1 inhibit MMP-2 and-9
respectively. Hence, FXR may represent a novel therapeutic target. Two
FXR agonists were used to measure their effects on breast cancer cells MDA-MB-231,
MDA-MB-468 (triple negative), MCF-7 (Estrogen receptor positive) and normal
cells MCF10A: CDCA is an endogenous, while GW4064 is a synthetic ligand. Cell
viability, protein and mRNA levels of matrix metalloprotease -2 and -9 and
TIMP-2 and-1, and cell migration were assessed using both molecular and
cellular techniques. Both FXR agonists decreased breast cancer and
normal breast cell viability, with the effects more significant in the triple
negative cells, suggesting a potential targeting towards aggressive cancer.
However, the FXR ligands didn’t alter mRNA and protein levels of MMP-2,
MMP-9, TIMP-1 and TIMP-2 intracellularlly or extracellularlly, suggesting
that this cytotoxic effect may not be via MMP. FXR ligands also had no effect
on breast cancer migration, which is consistent with the suggestion that FXR
activation has a general cytotoxic effect on tumour cells, but does not
directly impact on tumour migration. In conclusion, FXR activation doesn’t
impact on markers of breast cancer metastasis, suggesting that its potential
as a therapeutic target to prevent tumour progression may be limited.
However, the cytotoxic effect on cancer cells is promising, suggesting that
these agonists may still possess some potential for breast cancer therapy.
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المؤتمر (2):
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عنوان المؤتمر:
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7th Saudi
Students Conference
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تاريخ الإنعقاد:
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1-2/02/2014
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مكان
الإنعقاد:
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Edinburgh,
UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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Role
of Farnesoid X Receptor in Regulation of Metastatic Breast Cancer
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ملخص المشاركة:
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Breast cancer is a primary cause
of mortality in women and it is correlated to poor prognosis. Therefore,
understanding the molecular mechanisms of invasive cancers is fundamental for the
discovery of new generation of treatments. Degradation of extracellualr
matrix is required for the malignancies to invade and migrate to distant organs, and
that occurs by specific endopeptidases which are called Matrix
metalloproteinases (MMPs) with high expression of MMP-2 and -9 in metastatic breast
cancer in particular. MMP activity is tightly regulated by the tissue
inhibitors of metalloproteinases (TIMPs). Researchers have shown that
the nuclear receptor Farnesoid X-receptor (FXR) is involved in regulation of
MMP and TIMP activity in hepatic and vascular tissues. The rationale of the
current study was to investigate whether FXR is a novel regulator of MMP-2
and -9 as it is highly expressed in metastatic breast cancer. Initially the
viability of the breast cancer cell lines MCF7 (Estrogen receptor positive) and
MDA-MB-468 (The triple negative) was measured after exposure to the FXR
agonists chenodeoxycholic acid (CDCA) and 3-[2-[2-Chloro-4-[[3-(2,
6-dichlorophenyl)-5-(1-methylethyl)-4
isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid (GW4064). Our
findings showed that FXR ligands caused cell death and the effects were more
significant in the triple negative cells. Protein and mRNA levels of MMP-2
and -9 within both cell lines did not change after FXR activation, when measured by Western blotting
and real time PCR. Furthermore, the migratory response and the effect on
activity of MMP for FXR ligands are being investigated. Our finding suggests
that FXR activation is not pro-metastatic, but can kill tumour
cells, so it might be a novel therapeutic target for metastatic breast
cancer.
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المؤتمر (3):
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6th Saudi
Students Conference
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عنوان المؤتمر:
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11-14 /10
/2012
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تاريخ الإنعقاد:
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London, UK
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مكان
الإنعقاد:
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Poster presentation
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طبيعة المشاركة:
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FXR Regulates
Matrix Metalloproteinases in Breast Cancer
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عنوان المشاركة:
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Metastasis
is associated with poor prognosis in breast cancer. Thus it is crucial to
understand the molecular mechanisms of tumour cell invasion and metastasis in
order to identify therapeutic targets. Metastasis requires degradation of the
extracellular matrix (ECM), permitting cancer cells to invade and spread to
distant sites. Matrix metalloproteinases (MMPs) are essential for degrading
the proteins of the ECM. In particular, MMP-2 and -9 expression correlates
with poor breast cancer prognosis. MMP activity is regulated by the tissue
inhibitors of metalloproteinases (TIMPs). TIMP-1 inhibits MMP-9 whereas
TIMP-2 inhibits MMP-2. Studies have shown that the nuclear receptor Farnesoid
X receptor (FXR) is involved in MMP and TIMP regulation in hepatic and vascular
tissues and is highly expressed in breast cancer.
So the
aim of this project was to investigate whether FXR
is a novel regulator of MMP-2 and -9 in breast cancer cells.
Initially the cell viability of breast cancer
cell lines MCF7 (Estrogen receptor positive) and MDA-MB-468 (Estrogen
receptor negative) after treatment with FXR agonists CDCA and GW4064 were
measured. FXR ligands decreased the cell viability in both cell lines and the
effects were more significant in MDA-MB-468. The mRNA and protein levels of
MMP-2 and -9 within both cell lines did not change after FXR activation, when measured by real time
PCR and Western blotting. Interestingly, when the activity of the
MMP-2 and -9 enzymes secreted into the culture media was measured using a
fluorescent substrate; GW4064 increased MMP activity in a concentration
dependant manner, whereas CDCA had no effect. To determine whether this was
due to FXR regulation of TIMPs, their mRNA expression was measured by real
time PCR. There was no effect of FXR ligands on TIMP-1
and -2 mRNA levels.
In
conclusion, FXR activation by GW4064 increases secreted MMP-2 and -9 activity
in breast cancer cells but this effect is not via transcriptional regulation
of the MMPs or their inhibitory factors TIMP-1 or -2.
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المؤتمر (4):
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عنوان المؤتمر:
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International Society for the Study of Xenobiotics (ISSX)
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تاريخ الإنعقاد:
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17/06/2012
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مكان
الإنعقاد:
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Noordwijjk,
Netherlands
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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Regulation Of Matrix Metalloproteinases By FXR In Metastatic Breast
Cancer
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ملخص المشاركة:
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Metastasis is associated with poor prognosis in breast cancer. Thus it
is crucial to understand the molecular mechanisms of tumour cell invasion and
metastasis in order to identify therapeutic targets. Metastasis requires
degradation of the extracellular matrix (ECM), permitting cancer cells to
invade and spread to distant sites. Matrix metalloproteinases (MMPs) are
essential for degrading the proteins of the ECM. In particular, MMP-2 and -9
expression correlate with poor breast cancer prognosis. MMP activity is
regulated by the tissue inhibitors of metalloproteinases (TIMPs). TIMP-1
inhibits MMP-9 whereas TIMP-2 inhibits MMP-2. Studies have shown that the
nuclear receptor Farnesoid X receptor (FXR) is involved in MMP and TIMP
regulation in hepatic and vascular tissues and is highly expressed in breast
cancer1-3. So the aim of this project was to investigate whether
FXR is a novel regulator of MMP-2 and -9 in breast cancer cells. Initially
the cell viability of breast cancer cell lines MCF7 (Estrogen receptor
positive) and MDA-MB-468 (Estrogen receptor negative) after treatment with
FXR agonists chenodeoxycholic acid (CDCA) and3-[2-[2-Chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4
isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid, known as GW4064 were
measured. FXR ligands decreased the cell viability in both cell lines and the
effects were more significant in MDA-MB-468. The mRNA and protein levels of
MMP-2 and -9 within both cell lines did not change after FXR activation, when
measured by real time PCR and Western blotting. Interestingly, when the
activity of the MMP-2 and -9 enzymes secreted into the culture media
was measured using a fluorescent substrate; GW4064 increased MMP activity in
a concentration dependant manner, whereas CDCA had no effect. To determine
whether this was due to FXR regulation of TIMPs, their mRNA expression was
measured by real time PCR. There was no effect of FXR ligands on TIMP-1 and
-2 mRNA levels. In conclusion, FXR activation by GW4064 increases secreted
MMP-2 and -9 activity in breast cancer cells but this effect is not via transcriptional
regulation of the MMPs or their inhibitory factors TIMP-1 or -2.
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المؤتمر (5):
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عنوان المؤتمر:
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5th Saudi
Students Conference
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تاريخ الإنعقاد:
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23-26/06/2011
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مكان
الإنعقاد:
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Coventry,
UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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The Role of
Farnesoid X Receptor in Matrix Metalloproteinase Regulation in Breast Cancer
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Breast
cancer is a leading cause of female death in the UK. Therefore, developing
new drugs is crucial. The nuclear receptor FXR is a potential novel
therapeutic target. FXR is activated by bile acids, is
expressed and is pro-apoptotic in breast cancers. Matrix
metalloproteinases (MMP) 9 & 2 are enzymes involved in tissue
remodelling, key to invasion and metastasis of breast tumours.
Could FXR be a novel
regulator of MMP-2 and -9? Initial experiments were performed to establish
the effects of FXR ligands on the cell viability of breast cancer cell lines
MCF7 (Estrogen receptor positive) and MDA-MB-468 (Estrogen receptor
negative). The cells were 100% viable in the vehicle control. For MDA-MB-468, CDCA decreased cell viability
to 80 & 59% (10% serum conditions) and 62 & 33% (serum free
conditions) for 24h and 48h exposures respectively. In contrast, GW4064 only
decreased MDA-MB-468 viability under serum free conditions, to 75% (24h)
& 41% (48h). Similarly, CDCA
decreased MCF7 cell viability to almost 86%, under both serum and serum free
conditions at 24 and 48h time points. Whereas GW4064 only decreased MCF7
viability to 76% after 48h under serum-free conditions. These effects on cell
viability need to be considered during investigations into MMP regulation. MMP-2
&-9 activity were measured using a fluorescent substrate in conditioned
media collected from the cell viability experiments. GW4064 increased, whereas CDCA decreased
MMP activity in a concentration dependant manner. We are now investigating
these opposing results further. In addition we are measuring the protein and
mRNA levels of MMP-2 and -9 by Western blot and real-time PCR.
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