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17β-hydroxysteroid dehydrogenase 14 affects estradiol levels in breast cancer cells and is a prognostic marker in estrogen receptor-positive breast cancer
Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
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2006 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 66, no 23, 11471-11477 p.Article in journal (Refereed) Published
Abstract [en]

Estrogens have an important role in the progression of breast cancer. The 17β-hydroxysteroid dehydrogenase (17HSD) family has been identified to be of significance in hormone-dependent tissues. 17HSD1 and 17HSD2 are the main 17HSD enzymes involved in breast cancer investigated this far, but it is possible that other hormone-regulating enzymes have a similar role. 17HSD5 and 17HSD12 are associated with sex steroid metabolism, and 17HSD14 is a newly discovered enzyme that may be involved in the estrogen balance. The mRNA expression of 17HSD5, 17HSD12, and 17HSD14 were analyzed in 131 breast cancer specimens by semiquantitative real-time PCR. The results were compared with recurrence-free survival and breast cancer-specific survival of the patients. The breast cancer cell lines MCF7, SKBR3, and ZR75-1 were transiently transfected with 17HSD14 to investigate any possible effect on estradiol levels. We found that high 17HSD5 was related to significantly higher risk of late relapse in estrogen receptor (ER)-positive patients remaining recurrence-free later than 5 years after diagnosis (P = 0.02). No relation to 17HSD12 expression was found, indicating that 17HSD12 is of minor importance in breast cancer. Patients with ER-positive tumors with high expression levels of 17HSD14 showed a significantly better prognosis about recurrence-free survival (P = 0.008) as well as breast cancer-specific survival (P = 0.01), confirmed by multivariate analysis (P = 0.04). Transfection of 17HSD14 in the human breast cancer cells MCF7 and SKBR3 significantly decreased the levels of estradiol, presenting an effect of high expression levels of the enzyme. ©2006 American Association for Cancer Research.

Place, publisher, year, edition, pages
2006. Vol. 66, no 23, 11471-11477 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-36099DOI: 10.1158/0008-5472.CAN-06-1448Local ID: 29885OAI: oai:DiVA.org:liu-36099DiVA: diva2:256947
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
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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Available from: 2012-10-17 Created: 2012-10-17 Last updated: 2012-10-17Bibliographically approved

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Jansson, AgnetaGunnarsson, CeciliaCohen, MajaSivik, ToveStål, Olle

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OncologyFaculty of Health SciencesDepartment of Surgery in ÖstergötlandDepartment of Oncology UHL
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