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Title: Importance of carcinoma-associated fibroblasts in breast cancer and effects of CXCL12 and IGF-1 on malignant breast epithelial cells
Author: Hawsawi, Nahed Mohammed
ISNI:       0000 0004 2719 9152
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2011
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It has become clear that the phenotypic alterations present in carcinoma-associated fibroblasts play an important role in the development and progression of breast carcinomas. To investigate these alterations, a panel of carcinoma-associated fibroblast and their counterpart fibroblast primary cell cultures were assessed for their expression of p53, p21 and survivin. The induction of p53 and p21 in response to gamma-irradiation was defective in most of the carcinoma-associated fibroblasts but not in their counterpart fibroblasts. In addition, the constitutive levels of p53 and p21 proteins were significantly lower in most of the carcinoma-associated fibroblasts and modulated in the majority of tumour counterpart fibroblasts compared to the normal breast fibroblasts. Survivin expression was higher in both carcinoma-associated fibroblasts and tumour counterpart fibroblasts as compared to in normal fibroblasts. This part of the work demonstrates that carcinoma-associated fibroblasts have undergone premalignant changes that make them resistant to irradiation. The cytokine, CXCL12 is secreted by stromal cells and can affect the growth and progression of breast tumours. In malignant breast epithelial cells, CXCL12 mRNA has been shown to be expressed also and to be increased by oestrogen. To evaluate the importance of CXCL12 in the oestrogen response of breast cancer cells, the expression of CXCL12 and both its receptors, CXCR4 and CXCR7, was assessed by quantitative real time PCR and western transfer analysis in a panel of eleven human breast cancer cell lines. Notably CXCL12 was expressed mostly in the oestrogen-responsive breast cancer cell lines, whereas CXCR4 and CXCR7 were expressed at high levels in MDA-MB-231, an oestrogen non-responsive breast cancer cell line. Furthermore, oestrogen increased CXCL12 mRNA expression in breast cancer cell lines, while the expression of CXCR4 and CXCR7 mRNAs was decreased in response to oestrogen. The effects of CXCL12 on the proliferation and migration of breast cancer cells were tested. The results of these experiments showed that CXCL12 has a motogenic effect in both oestrogen-responsive and oestrogen non-responsive breast cancer cells. Interestingly, the combined effect of CXCL12 and IGF-1 was more than additive on migration of breast cancer cells. Furthermore, phosphorylation of CXCR4, and its downstream effectors, Akt and MAPK, was studied in oestrogen-responsive breast cancer cells, ZR-75 cells, and oestrogen non-responsive breast cancer cells, MDA-MB-231 cells. Our results suggest that the phosphorylation of Akt and MAPK may be involved in mediating the effects of CXCL12 in breast cancer cells. The work described in the second part the thesis emphasis the importance of the interplay between oestrogen, CXCL12 and IGF-1 in the responsiveness of malignant breast epithelial cells.
Supervisor: Not available Sponsor: King Khalid Foundation ; King Faisal Specialist Hospital and Research Centre
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available