17β-Hydroxysteroid Dehydrogenase Type 14 Is a Predictive Marker for Tamoxifen Response in Oestrogen Receptor Positive Breast Cancer

Sivik, Tove; Gunnarsson, Cecilia; Fornander, Tommy; Nordenskjöld, Bo; Skoog, Lambert; Stål, Olle; Jansson, Agneta

doi:10.1371/journal.pone.0040568

Cited by 20 publications

(13 citation statements)

References 16 publications

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“…The extent to which individual enzymes of this family have been studied varies. The relevance of the 17βHSD14 protein in normal physiology has not been addressed, although we have previously shown tumoral expression of both HSD17B14 mRNA and the 17βHSD14 protein to be of importance in breast cancer, both for predicting prognosis [ 21 ] and in predicting tamoxifen treatment response [ 22 ] . In both cases, 17βHSD14 appears to be a factor predicting good clinical outcome in breast cancer; however, functional mechanisms underlying this remain elusive.…”

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confidence: 99%

Expression Patterns of 17β-Hydroxysteroid Dehydrogenase 14 in Human Tissues

et al. 2012

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2 17βHSD enzymes catalyse the stereospecific oxidation/reduction at carbon 17β of androgens and 3 oestrogens, and are important players in intracrine sex hormone synthesis. The biological relevance of 4 17βHSD14, first named retSDR3, is largely unknown. We generated and validated an antibody 5 targeting the 17βHSD14 antigen and used this for immunohistochemical evaluation of expression 6 patterns in 33 healthy human tissues. Furthermore, sex steroid conversional activity in HSD17B14 7 over-expressing HEK293 and MCF10A cells was investigated by assessing interconversion products 8 of oestrone, oestradiol, androstenedione, testosterone and dehydroepiandrosterone. 9Immunohistochemical staining patterns of 17βHSD14 with the enzyme being primarily expressed in 10 glandular epithelial tissue reveal an enzyme with possible implications in the secretion or conversion 11 of externally derived compounds. A role for 17βHSD14 in sex steroid metabolism is supported by the 12 finding that 17HSD14 oxidises both oestradiol and testosterone into less bioactive steroid metabolites 13 oestrone and androstenedione respectively. 14 15

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Expression Patterns of 17β-Hydroxysteroid Dehydrogenase 14 in Human Tissues

et al. 2012

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“… 28 However, little is known of the relationship between the various 17β HSD isoforms and glaucoma, particularly the product of HSD17B14 , which was first discovered in the human retina 29 and predicts a favorable response to tamoxifen in estrogen receptor–positive breast cancer tissue. 30 As for 17β HSD isoforms 7 and 12, which were associated with HTG only in the US dataset, they are involved in local production of estradiol and feature prominently in the endoplasmic reticulum, 31 whose subcellular organelles are abundant in the trabecular meshwork. 32 More work is needed to understand if and how testosterone metabolism and functional polymorphisms in the various 17β HSD enzymes contribute to endoplasmic reticulum stress found in POAG.…”

Section: Discussionmentioning

confidence: 99%

Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets

Bailey

Gharahkhani

Kang

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeSex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk.MethodsWe used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG]).ResultsIn the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations.ConclusionsCollectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

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“…The predominant isoform with oxidative 17β-HSD activity in the endometrium is HSD17B2, which converts active T to A4. Expression of HSD17B2 is increased by progesterone and elevated in the secretory phase [4,43]. HSD17B14 also has oxidative 17β-HSD activity and has been immunolocalised to endometrial glandular epithelial cells [44] although relative efficiency for oxidation of E2 or T was much lower than that of HSD17B2 in cell metabolism assays.…”

Section: Androgen Activation and Metabolismmentioning

confidence: 98%

Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders

Gibson¹,

Simitsidellis²,

Collins³

et al. 2018

Preprint

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Peripheral tissue metabolism of steroids (intracrinology) is now accepted as a key way in which tissues, such as the endometrium, can utilize inactive steroids present in the blood to respond to local physiological demands and ‘fine-tune’ the activation or inhibition of steroid hormone receptor-dependent processes. Expression of enzymes that play a critical role in activation and inactivation of bioactive oestrogens (E1, E2) and androgens (A4, T, DHT), as well as expression of steroid hormone receptors, has been detected in endometrial tissues and cells recovered during the menstrual cycle. There is robust evidence that increased expression of aromatase is important for creating a local microenvironment that can support a pregnancy. Measurement of intra-tissue concentrations of steroids using liquid chromatography–tandem mass spectrometry has been important in advancing our understanding of a role for androgens in the endometrium acting both as active ligands for the androgen receptor and as substrates for oestrogen biosynthesis. The emergence of intracrinology, associated with disordered expression of key enzymes such as aromatase, in the aetiology of common women’s health disorders such as endometriosis and endometrial cancer has prompted renewed interest in development of drugs targeting these pathways opening up new opportunities for targeted therapies and precision medicine.   

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17β-Hydroxysteroid Dehydrogenase Type 14 Is a Predictive Marker for Tamoxifen Response in Oestrogen Receptor Positive Breast Cancer

Cited by 20 publications

References 16 publications

Expression Patterns of 17β-Hydroxysteroid Dehydrogenase 14 in Human Tissues

Expression Patterns of 17β-Hydroxysteroid Dehydrogenase 14 in Human Tissues

Testosterone Pathway Genetic Polymorphisms in Relation to Primary Open-Angle Glaucoma: An Analysis in Two Large Datasets

Endometrial Intracrinology: Oestrogens, Androgens and Endometrial Disorders

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