Estrogen and androgen-converting enzymes 17β-hydroxysteroid dehydrogenase and their involvement in cancer: with a special focus on 17β-hydroxysteroid dehydrogenase type 1, 2, and breast cancer.

Erik Hilborn,Agneta Jansson,Olle Stål

doi:10.18632/oncotarget.15547

Erik Hilborn, Agneta Jansson + Show 1 more

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https://doi.org/10.18632/oncotarget.15547

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Journal: Oncotarget	Publication Date: Feb 20, 2017
Citations: 83	License type: cc-by

Affiliation: Linköping University

Abstract

Sex steroid hormones such as estrogens and androgens are involved in the development and differentiation of the breast tissue. The activity and concentration of sex steroids is determined by the availability from the circulation, and on local conversion. This conversion is primarily mediated by aromatase, steroid sulfatase, and 17β-hydroxysteroid dehydrogenases. In postmenopausal women, this is the primary source of estrogens in the breast. Up to 70-80% of all breast cancers express the estrogen receptor-α, responsible for promoting the growth of the tissue. Further, 60-80% express the androgen receptor, which has been shown to have tissue protective effects in estrogen receptor positive breast cancer, and a more ambiguous response in estrogen receptor negative breast cancers. In this review, we summarize the function and clinical relevance in cancer for 17β-hydroxysteroid dehydrogenases 1, which facilitates the reduction of estrone to estradiol, dehydroepiandrosterone to androstendiol and dihydrotestosterone to 3α- and 3β-diol as well as 17β-hydroxysteroid dehydrogenases 2 which mediates the oxidation of estradiol to estrone, testosterone to androstenedione and androstendiol to dehydroepiandrosterone. The expression of 17β-hydroxysteroid dehydrogenases 1 and 2 alone and in combination has been shown to predict patient outcome, and inhibition of 17β-hydroxysteroid dehydrogenases 1 has been proposed to be a prime candidate for inhibition in patients who develop aromatase inhibitor resistance or in combination with aromatase inhibitors as a first line treatment. Here we review the status of inhibitors against 17β-hydroxysteroid dehydrogenases 1. In addition, we review the involvement of 17β-hydroxysteroid dehydrogenases 4, 5, 7, and 14 in breast cancer.

Highlights

Sex steroid hormones such as estrogens and androgens are involved in the development and differentiation of several tissues and organs, including bone, cardiovascular, brain and gender-specific sites such as testis, prostate, endometrium, and ovaries
Steroid hormones are pivotal in determining the future of tissues exposed to them, and 17β-hydroxysteroid dehydrogenase (HSD17B), especially 1 and 2, are important components in mediating the local concentrations of steroids in tissues where they are expressed
The evidence is mounting that they are involved in several forms of cancer, and the expression pattern of HSD17Bs differs greatly in cancer as opposed to healthy tissue

Summary

Introduction

Sex steroid hormones such as estrogens and androgens are involved in the development and differentiation of several tissues and organs, including bone, cardiovascular, brain and gender-specific sites such as testis, prostate, endometrium, and ovaries. In vivo studies using cell lines in rats and mice, as well as clinical studies have shown that the preferential reaction is reductive, and HSD17B1 expression has been found to be increased in breast cancer compared with unchanged tissue. Studies using breast cancer cells where HSD17B1 was downregulated show a significant reduction in proliferation and lowered E2 concentrations, and accompanied by increased DHT levels, likely as a result of the loss of E1 to E2 and DHT to 3α/3β-diol conversion by HSD17B1 [39, 46, 60].

Results

Conclusion