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Title: Cytochrome P450 mRNA profile in human breast cancer cell lines
Authors: Warasiha, Benjamart
Supervisors: McFadyen, Morag
Knott, Rachel M.
Keywords: Cytochrome P450 mRNA
Cytochrome P450-regulatory nuclear receptor
Oestrogen receptor (ER)-positive and negative breast cancer cell lines (BCCs)
Caucasian and Afro-Caribbean BCCs
CYP4Z1 alternative splicing
Regulation of CYP4Z1
Issue Date: May-2008
Publisher: The Robert Gordon University
Citation: WARASIHA, B., KNOTT, R. and BOYLE, S., 2004. Investigation of the role of xenobiotic metabolising enzymes in breast cancer development. The Journal of Nutrition, 134 (12 Suppl), pp. 3525S
WARASIHA, B., KNOTT, R. and MCFADYEN, M., 2007. Comparative analysis of Cytochrome P450 mRNA expression between human caucasian and Afro-Caribbean breast cancer cell lines. In:Proceedings of the National Cancer Research Institute (NCRI) Cancer conference. October 2007. Birmingham: ICC.
WARASIHA, B., KNOTT, R. and MCFADYEN, M., 2007. Differential cytochrome P450 mRNA profile between non-invasive and invasive breast cancer phenotypes. In: Proceedings of National Cancer Research Institute (NCRI) cancer conference. October 2007. Birmingham: ICC.
KAY, G., CAIRNS, D., MCCAUGHAN, B. and WARASIHA, B., 2007. The design, synthesis and biological evaluation of novel prodrugs for th treatment of cystinosis. In: Proceedings of the British Conference Pharmaceutical (BCP), September 2007. Manchester.
KAY, G., WARASIHA, B., MELVILLE, M. and MINCHER, D. J., 2007. Design, synthesis and biological evaluation of novel DNA binding agents. In: Proceedings of the British Conference Pharmaceutical (BCP), September 2007. Manchester.
WARASIHA, B., KNOTT, R. and MCFADYEN, M., 2006. Profile of cytochrome P450 mRNA expression in oestrogen positive and negative breast cancer cell lines. In: Proceedings of National Cancer Research Institute (NCRI) cancer conference, October 2006. Birmingham: ICC.
Abstract: Cytochrome P450 enzymes (P450s) are involved in cancer development and treatment due to their roles in the oxidative metabolism of various endogenous (e.g. oestrogen) and exogenous (e.g. tamoxifen) compounds. It is well-known that intermediate P450 metabolites derived from oestrogen metabolism are associated with breast carcinogenesis. The main aim of this project was to profile the cytochrome P450 and P450-regulatory nuclear receptor mRNAs in a series of breast cancer cell lines (BCCs) and compare this profile with normal breast cells. This study used the qualitative reverse transcriptasepolymerase chain reaction (RT-PCR) to detect mRNA expression of target genes. Results showed CYP1B1, CYP2D6, CYP2J2, CYP2R1, CYP2U1 and CYP4X1 mRNA to be present in all cell lines. CYP2A6, CYP2C8, CYP2C18, CYP2F1 and CYP4Z1 mRNA were expressed in oestrogen receptor (ER)-positiveCaucasian and ER-negative Afro- Caribbean BCCs. Although no differences in P450 mRNA were observed between the different ethnic groups, these preliminary findings suggest potential similarities in the ERpositive Caucasian and ER-negative Afro-Caribbean BCCs which warrant further investigation The CYP4Z1 PCR product was identified as two distinct bands. Specific primer sets were used to demonstrate potential intron retention in CYP4Z1. Using established in vitro models for the study of regulatory mechanisms of CYP4Z1, T47D and ZR-75-1 breast cancer cell lines were used to determine the appropriate nuclear receptors (i.e. progesterone receptor, glucocorticoid receptor or peroxisome proliferator-activated receptor alpha ). These findings suggest that there may be an alternative receptor mechanism involved in CYP4Z1 mRNA induction in these cells. In conjunction, pre-treatment of these two cell lines with the RNA synthesis inhibitor actinomycin D followed by the agonists showed a significant reduction (p < 0.05) of CYP4Z1 mRNA levels and inhibited CYP4Z1 induction by either progesterone, dexamethasone or pirinixic acid, indicating that these agonists have effects on CYP4Z1 mRNA transcription or stability. In contrast, cycloheximide differentially affected the level of CYP4Z1 mRNA induction by these agonists. Taken together, these results suggest that CYP4Z1 mRNA induction in T47D and ZR-75-1 is mediated through differential cell type specific regulatory mechanisms and there is evidence for differential regulation of the splice variants.
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