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البحوث المنشورة

البحث (1):

عنوان البحث:

Activation of the Farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential

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تاريخ النشر:

03/11/2015

موجز عن البحث:

المؤتمرات العلمية:

المؤتمر (1):

عنوان المؤتمر:

8^th Saudi Students Conference

تاريخ الإنعقاد:

31/01-01/02/2015

مكان الإنعقاد:

London, UK

طبيعة المشاركة:

Poster presentation

عنوان المشاركة:

Farnesoid X Receptor role on modulation of Matrix Metalloproteinases -2 and -9 in Metastatic Breast Cancer

ملخص المشاركة:

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.

المؤتمر (2):

عنوان المؤتمر:

7^th Saudi Students Conference

تاريخ الإنعقاد:

1-2/02/2014

مكان الإنعقاد:

Edinburgh, UK

طبيعة المشاركة:

Poster presentation

عنوان المشاركة:

Role of Farnesoid X Receptor in Regulation of Metastatic Breast Cancer

ملخص المشاركة:

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.

المؤتمر (3):

6^th Saudi Students Conference

عنوان المؤتمر:

11-14 /10 /2012

تاريخ الإنعقاد:

London, UK

مكان الإنعقاد:

Poster presentation

طبيعة المشاركة:

FXR Regulates Matrix Metalloproteinases in Breast Cancer

عنوان المشاركة:

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.

المؤتمر (4):

عنوان المؤتمر:

International Society for the Study of Xenobiotics (ISSX)

تاريخ الإنعقاد:

17/06/2012

مكان الإنعقاد:

Noordwijjk, Netherlands

طبيعة المشاركة:

Poster presentation

عنوان المشاركة:

Regulation Of Matrix Metalloproteinases By FXR In Metastatic Breast Cancer

ملخص المشاركة:

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 cancer^1-3. 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.

المؤتمر (5):

عنوان المؤتمر:

5^th Saudi Students Conference

تاريخ الإنعقاد:

23-26/06/2011

مكان الإنعقاد:

Coventry, UK

طبيعة المشاركة:

Poster presentation

عنوان المشاركة:

The Role of Farnesoid X Receptor in Matrix Metalloproteinase Regulation in Breast Cancer

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.