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

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.

Intracrine Regulation of Estrogen and Other Sex Steroid Levels in Endometrium and Non-gynecological Tissues; Pathology, Physiology, and Drug Discovery

“…A brief non-systematic description of the intracrinology of the skin, immune system and adipose tissue is also given. We will not describe the intracrinology of breast, prostate and liver (where steroid catabolism is the most relevant aspect), and we redirect the reader to recent reviews (Foster et al, 2008a ; Luu-The et al, 2008 ; Luu-The and Labrie, 2010 ; Labrie and Labrie, 2013 ; Labrie, 2015 ; Mueller et al, 2015 ; Zhao et al, 2016 ; Hilborn et al, 2017 ; Penning, 2017 ).…”

Melatonin: A Molecule for Reducing Breast Cancer Risk

“…Estrogen sulfates can serve to form active (non-sulfated) estrogens [ 28 ]. Another family of enzymes, the 17β-hydroxysteroid dehydogenases types I and II, catalyzes the conversion of low activity steroids (androstenedione and estrone) into high activity steroids (testosterone and 17β-estradiol respectively) (see Figure 1 ) [ 29 , 30 ]. Contrary to what happens in normal mammary tissue, in breast cancer, the local production of steroids is biased toward the production of the more active forms (a fact indicated by the thickness of the arrows in Figure 1 ) [ 26 ].…”

The regulation of hydroxysteroid 17β-dehydrogenase type 1 and 2 gene expression in breast cancer cell lines by estradiol, dihydrotestosterone, microRNAs, and genes related to breast cancer

“…The persistent effect of dihydrotestosterone on T-47D combined with the small but sizable increase in HSD17B2 expression in SK-BR-3, suggests that AR is not the only component in mediating dihydrotestosterone driven changes in HSD17B2. The presence of ERβ1 [ 32 ], which may be activated by 3α- and 3β-diol [ 33 ], may be an explanation for this, but further evaluation is needed.…”