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Characterisation of Hsd17b14 knockout mice
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-5194-2124
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

17β hydroxysteroid dehydrogenase (17βHSD) enzymes catalyse the stereospecific oxidation/reduction at carbon 17β of androgens and oestrogens and thereby regulate the pool of bioactive sex hormones. 17βHSD type 14 (17βHSD14) catalyses the inactivation of 17β-hydroxysteroids into their less bioactive 17-keto formation in vitro, however, as the catalytic efficiency of this reaction is relatively low, the question is whether this reaction is the biological role of the enzyme in vivo, or if the enzyme additionally or altogether acts within alternative metabolic pathways. To investigate the role of 17βHSD14 in vivo, we studied the phenotype of a mouse model in which the Hsd17b14 gene had been targeted through homologous recombination. Tissues from male and female mice sacrificed at 3-4 months of age were collected and analysed with regards to gene expression of Hsd17b14 and Hsd17b2 and histological appearance of selected organs. Wild type animals expressed Hsd17b14 in a large number of tissues, peaking in reproductive tissues. Mice globally lacking Hsd17b14 were grossly morphologically identical to their WT counterparts. The histological examination however, revealed impaired mammary gland branching and increased hepatocellular vacuolisation in Hsd1714 knockout animals compared with their WT counterparts. In conclusion, while phenotypical aberrances were absent in most tissues, which may be the result of genetic redundancy or possibly an indication that the gene in question is only modulatory, the main differences, primarily a mammary gland phenotype in female KO mice, implicate disturbed hormonal homeostasis, and thus a role for Hsd17b14 in steroidogenesis in vivo.

National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-84683OAI: oai:DiVA.org:liu-84683DiVA: diva2:561157
Available from: 2012-10-17 Created: 2012-10-17 Last updated: 2015-03-12Bibliographically approved
In thesis
1. Elucidating the role of 17β hydroxysteroid dehydrogenase type 14 in normal physiology and in breast cancer
Open this publication in new window or tab >>Elucidating the role of 17β hydroxysteroid dehydrogenase type 14 in normal physiology and in breast cancer
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Oestrogens play key roles in the development of the majority of breast tumours, a fact that has been exploited successfully in treating breast cancer with tamoxifen, which is a selective oestrogen receptor modulator. In post-menopausal women, oestrogens are synthesised in peripheral hormone-target tissues from adrenally derived precursors. Important in the peripheral fine-tuning of sex hormone levels are the 17β hydroxysteroid dehydrogenases (17βHSDs). These enzymes catalyse the oxidation/reduction of carbon 17β of androgens and oestrogens. Upon receptor binding, the 17β-hydroxy conformation of androgens and oestrogens (testosterone and oestradiol) triggers a greater biological response than the corresponding keto-conformation of the steroids (androstenedione and oestrone), and the 17βHSD enzymes are therefore important mediators in pre-receptor regulation of sex hormone action.

Breast tumours differ substantially with regards to molecular and/or biochemical signatures and thus clinical courses and response to treatment. Predictive factors, which aim to foretell the response of a patient to a specific therapeutic intervention, are therefore important tools for individualisation of breast cancer therapy. This thesis focuses on 17βHSD14, which is one such proposed marker, aiming to learn more of properties of the enzyme in breast cancer as well as in normal physiology. We found that high 17βHSD14 levels were correlated with clinical outcome in two separate subsets of breast tumour materials from trials evaluating adjuvant tamoxifen therapy. Striving to understand the underlying mechanisms, immunohistochemical 17βHSD14 expression patterns were analysed in a large number of human tissues using an in-house generated and validated antibody. The 17βHSD14 protein was expressed in several classical steroidogenic tissues such as breast, ovary and testis which supports idea of 17βHSD14 being an actor in sex steroid interconversion. Furthermore, using a radio-high pressure liquid chromatography method, cultured cells transiently expressing HSD17B14 were found to oxidise both oestradiol and testosterone to their less potent metabolites oestrone and androstenedione respectively. The evaluation of a mouse model lacking Hsd17b14 revealed a phenotype with impaired mammary gland branching and hepatic vacuolisation which could further suggest a role for 17βHSD14 in oestrogen regulation.

Although other mechanisms of the enzyme cannot be ruled out, we suggest that 17βHSD14 relevance in tamoxifen-treated breast cancer is related to oestradiol-lowering properties of the enzyme which potentiate the anti-proliferative effects of tamoxifen. Translating into the clinical setting, patients with oestrogen receptor positive tumours expressing low levels of oestradiol-oxidising enzymes such as 17βHSD14 would likely receive more clinical benefit from alternative treatments to tamoxifen such as aromatase inhibitors or in the future possibly inhibitors of reductive 17βHSD-enzymes.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 67 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1339
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84686 (URN)978-91-7519-763-0 (ISBN)
Public defence
2012-11-09, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
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Supervisors
Available from: 2012-10-17 Created: 2012-10-17 Last updated: 2012-10-17Bibliographically approved

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Sivik, ToveHilborn, ErikRodriguez-Martinez, HeribertoJansson, Agneta

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