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Elucidating the role of 17β hydroxysteroid dehydrogenase type 14 in normal physiology and in breast cancer
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-84686ISBN: 978-91-7519-763-0 (print)OAI: oai:DiVA.org:liu-84686DiVA: diva2:561164
Public defence
2012-11-09, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2012-10-17 Created: 2012-10-17 Last updated: 2012-10-17Bibliographically approved
List of papers
1. 17β-hydroxysteroid dehydrogenase 14 affects estradiol levels in breast cancer cells and is a prognostic marker in estrogen receptor-positive breast cancer
Open this publication in new window or tab >>17β-hydroxysteroid dehydrogenase 14 affects estradiol levels in breast cancer cells and is a prognostic marker in estrogen receptor-positive breast cancer
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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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-36099 (URN)10.1158/0008-5472.CAN-06-1448 (DOI)29885 (Local ID)29885 (Archive number)29885 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
2. Expression Patterns of 17β-Hydroxysteroid Dehydrogenase 14 in Human Tissues
Open this publication in new window or tab >>Expression Patterns of 17β-Hydroxysteroid Dehydrogenase 14 in Human Tissues
2012 (English)In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 44, no 13, 949-956 p.Article in journal (Refereed) Published
Abstract [en]

17βHSD enzymes catalyze the stereospecific oxidation/reduction at carbon 17β of androgens and estrogens, and are important players in intracrine sex hormone synthesis. The biological relevance of 17βHSD14, first named retSDR3, is largely unknown. We generated and validated an antibody targeting the 17βHSD14 antigen and used this for immunohistochemical evaluation of expression patterns in 33 healthy human tissues. Furthermore, sex steroid conversional activity in HSD17B14 overexpressing HEK293 and MCF10A cells was investigated by assessing interconversion products of estrone, estradiol, androstenedione, testosterone, and dehydroepiandrosterone. Immunohistochemical staining patterns of 17βHSD14 with the enzyme being primarily expressed in glandular epithelial tissue reveal an enzyme with possible implications in the secretion or conversion of externally derived compounds. A role for 17βHSD14 in sex steroid metabolism is supported by the finding that 17HSD14 oxidizes both estradiol and testosterone into less bioactive steroid metabolites estrone and androstenedione, respectively.

Place, publisher, year, edition, pages
Georg Thieme Verlag KG, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-84681 (URN)10.1055/s-0032-1321815 (DOI)000312501800004 ()22864907 (PubMedID)
Available from: 2012-10-17 Created: 2012-10-17 Last updated: 2017-12-07Bibliographically approved
3. 17β-hydroxysteroid dehydrogenase type 14 is a predictive marker for tamoxifen response in oestrogen receptor positive breast cancer
Open this publication in new window or tab >>17β-hydroxysteroid dehydrogenase type 14 is a predictive marker for tamoxifen response in oestrogen receptor positive breast cancer
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, e40568- p.Article in journal (Refereed) Published
Abstract [en]

Introduction: 17β-hydroxysteroid dehydrogenases (17βHSDs) are important enzymes regulating the pool of bioactive steroids in the breast. The current study was undertaken in order to evaluate implications of 17βHSD14 in breast cancer, measuring 17βHSD14 protein expression in breast tumours.

Methods: An antibody targeting the 17βHSD14 antigen was generated and validated using HSD17B14-transfected cells and a peptide-neutralising assay. Tissue microarrays with tumours from 912 post-menopausal women diagnosed with lymph node-negative breast cancer, and randomised to adjuvant tamoxifen or no endocrine treatment, were analysed for 17βHSD14 protein expression with immunohistochemistry.

Results: Results were obtained from 847 tumours. Patients with oestrogen positive tumours with high 17βHSD14 expression had fewer local recurrences when treated with tamoxifen (HR 0.38; 95% C.I. 0.19–0.77, p = 0.007) compared to patients with lower tumoural 17βHSD14 expression, for whom tamoxifen did not reduce the number of local recurrences (HR 1.19; 95% C.I. 0.54–2.59; p = 0.66). No prognostic importance of 17βHSD14 was seen for systemically untreated patients.

Conclusions: Using a highly specific validated antibody for immunohistochemical analysis of a large number of breast tumours, we have shown that tumoural expression levels of 17βHSD14 can predict the outcome of adjuvant tamoxifen treatment in terms of local recurrence-free survival in patients with lymph node-negative ER+ breast cancer. The results need be verified to confirm any clinical relevance.

Place, publisher, year, edition, pages
Plos ONE, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-80247 (URN)10.1371/journal.pone.0040568 (DOI)
Available from: 2012-08-23 Created: 2012-08-23 Last updated: 2017-12-07
4. Characterisation of Hsd17b14 knockout mice
Open this publication in new window or tab >>Characterisation of Hsd17b14 knockout mice
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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:nbn:se:liu:diva-84683 (URN)
Available from: 2012-10-17 Created: 2012-10-17 Last updated: 2015-03-12Bibliographically approved

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