Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485672
Title: Modulation of genes involved in the apoptotic pathway in human breast cancer by conjugated linoleic acid and other dietary fatty acids
Author: Majumder, Barun
ISNI:       0000 0001 3617 1002
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2005
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Abstract:
Dietary Eicosapentaenoic Acid (EPA), Conjugated Linoleic Acid (CLA) and Oleic Acid (OA) have been postulated to reduce the risk of breast cancer. This study has examined the effects of these dietary fatty acids on the induction of apoptosis in normal breast epithelial (MCF-l0A), oestrogen receptor positive (MCF-7) and oestrogen receptor negative breast cancer cells (MDA-MB-231). Cell proliferation was assessed using the MIT assay, and the comet assay was used to examine the extent ofDNA damage (as a marker of apoptosis). Changes in the expression of mRNA and the proteins of the major pro-apoptotic p53, p21WAF1/CIP1, bax, bcl-Xs genes and the anti-apoptotic bcl-2 gene were determined in these cell lines in titro. (' The greatest cell growth inhibition and induction of apoptosis was observed after exposure to CLA. Further investigations focussed on the mechanisms underlying the anti-tumour effects of CLA. CLA increased p53 and p21WAF1/CIPl mRNA expression (3-5-fold and 2-fold respectively) and decreased bcl-2 by 20-30%. Protein expression reflected the changes in mRNA expression. In the MDA-1ffi-231 cells (which express mutant p53), mRNA for p53 remained unchanged but p21WAF1/CIPl and bcl-2 mRNA was increased (1.6-fold and 2-fold respectively). Protein expression largely reflected mRNA changes but CLA completely suppressed mutant p53 protein in the MDA-1ffi-231 cells. On the other hand, in the MCF-7 cells, CLA significantly regulated both the mRNA and the proteins p53 and p21WAF1/CIPl (a'p53-dependent pathway). The apparent anti-apoptotic effects of increased bcl-2 expression in the MDA-MB-231 cells were countered by the pro-apoptotic p21WAF1/CIP1, Bax and Bcl-Xs proteins. These findings suggest that CLA elicits mainly pro-apoptotic effects in human breast tumour cells through both p53-dependent and p53-independent pathways, according to the cell type. EPA inhibited the breast cell line at high concentrations only (>100JlM) without increasing the apoptotic index in these cell lines, indicating an involvement of different cell signalling pathways to account for its anti-tumour properties. Oleic acid, however, had a variable effect on breast tumour growth. Dietary Eicosapentaenoic Acid (EPA), Conjugated Linoleic Acid (CLA) and Oleic. Acid (OA) have been postulated to reduce the risk of breast cancer. This study has examined the effects of these dietary fatty acids on the induction of apoptosis in normal breast epithelial (MCF-l0A), oestrogen receptor positive (MCF-7) and oestrogen receptor negative breast cancer cells (MDA-MB-231). Cell proliferation was assessed using the MIT assay, and the comet assay was used to examine the extent ofDNA damage (as a marker of apoptosis). Changes in the expression of mRNA and the proteins of the major pro-apoptotic pS3, p21WAF1/CIP1, bax, bcl-Xs genes and the anti-apoptotic bcl-2 gene were determined in these cell lines in vitro. .. The greatest cell growth inhibition and induction of apoptosis was observed after exposure to CLA. Further investigations focussed on the mechanisms underlying the anti-tumour effects of CLA. CLA increased pS3 and p21WAF1/CIPl mRNA expression (3-S-fold and 2-fold respectively) and decreased bcl-2 by 20-30%. Protein expression reflected the changes in mRNA expression. In the MDA-MB-231 cells (which express mutant pS3), mRNA for pS3 remained unchanged but p21WAF1/CIPl and bcl-2 mRNA was increased (lo6-fold and 2-fold respectively). Protein expression largely reflected mRNA changes but CLA completely suppressed mutant pS3 protein in the MDA-MB-231 cells. On the other hand, in the MCF-7 cells, CLA significandy regulated both the mRNA and the proteins p53 and p21WAFl / CIPl (a'pS3-dependent pathway). The apparent anti-apoptotic effects of increased bcl-2 expression in the MDA-MB-231 cells were countered by the pro-apoptotic p21WAF1/CIP1, Bax and Bcl-Xs proteins. These findings suggest that CLA elicits mainly pro-apoptotic effects in human breast tumour cells through both pS3-dependent and pS3-independent pathways, according to the cell type. EPA inhibited the breast cell line at high concentrations only (>100j.lM) without increasing the apoptotic index in these cell lines, indicating an involvement of different cell signalling pathways to account for its anti-tumour properties. Oleic acid, however, had a variable effect on breast tumour growth.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.485672  DOI: Not available
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