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Tissue-specific regulation of CYP19A1 – Implications for toxicological screening methods and breast cancer treatment strategies
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
2013 (English)Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Abstract [en]

Abstract

Background: Aromatase, encoded by CYP19A1, is an enzyme that converts androgens to estrogens. The enzyme is expressed in various tissues in the human body. The aim of this study is to investigate if there is a tissue-specific effect of 1α,25-dihydroxyvitamin D3 by analyzing the gene expression of CYP19A1 in cell lines representing the human adrenal cortex, the human ovarian, human osteoblastic cells and human breast glands. The results could be important for the evaluation of the NCI-H295R cell line as a toxicological screening method in which aromatase is an important enzyme and in the development of endocrine cancer therapy with CYP19A1 as a target.Methods: The change in gene expression followed exposure for 1α,25-dihydroxyvitamin D3 was measured  using qRT-PCR. Primers were specific for the total aromatase gene or promoter-specific regions of the gene.Results: The results show that 1α,25-dihydroxyvitamin D3 exerts a tissue specific effect on CYP19A1 expression. The gene expression was increased in the ovarian cells, the osteoblastic cells and the adrenocarcinoma cells, while it was decreased in the breast cancer cells. The results also showed an altered gene expression due to a promoter-specific regulation.Conclusion: It has become more clear that 1α,25-dihydroxyvitamin D3 could be a potential anti-breast cancer agent in the future. However, the difference in aromatase gene expression between the breast cancer cells and the adrenocarcinoma NCI-H295R cells indicates that the NCI-H295R cell line might not be reliable for toxicological screening on sex hormone production on its own, unless there is a way to take into account the tissue-specific regulation of CYP19A1.

Place, publisher, year, edition, pages
2013. , 23 p.
Keyword [en]
CYP19A1, vitamin d, 1α, 25-dihydroxyvitamin D3, calcitriol, H295R, MCF-7, T-47D, PEO14, hOB, qRT-PCR, breast cancer
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-202018OAI: oai:DiVA.org:uu-202018DiVA: diva2:630444
External cooperation
Sveriges lantbruksuniversitet
Subject / course
Toxicology
Educational program
Master of Science Programme in Pharmacy
Supervisors
Examiners
Available from: 2013-06-19 Created: 2013-06-19 Last updated: 2013-06-19Bibliographically approved

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