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Estrogen and Androgen-Converting Enzymes 17Β-Hydroxysteroid Dehydrogenase and Their Involvement in Cancer

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Estrogen and Androgen-Converting Enzymes 17Β-Hydroxysteroid Dehydrogenase and Their Involvement in Cancer www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 18), pp: 30552-30562 Review 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 Hilborn1, Olle Stål1 and Agneta Jansson1 1 Department of Clinical and Experimental Medicine and Department of Oncology, Faculty of Health Sciences, Linköping University, Linköping, Sweden Correspondence to: Erik Hilborn, email: [email protected] Keywords: breast cancer, estrogens, androgens, HSD17B1, HSD17B2 Received: September 23, 2016 Accepted: February 12, 2017 Published: February 20, 2017 Copyright: Hilborn et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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. INTRODUCTION is dependent on the circulating concentrations of the respective steroid, but also on local conversion. Sex steroid hormones such as estrogens and The effect of sex steroids on breast tissue in genetic androgens are involved in the development and females is normally primarily mediated by estrogens, differentiation of several tissues and organs, including with estradiol being the most active estrogen. Estrogen bone, cardiovascular, brain and gender-specific sites signaling results in breast growth, and changes in estrogen such as testis, prostate, endometrium, and ovaries. exposure occur naturally in the different stages of life, Steroids continuously assert their influence based on such as puberty and pregnancy. The effect of androgens relative concentration and exposure time, which in turn in breast tissue, with dihydrotestosterone (DHT) being the most potent, are in direct opposition to those of www.impactjournals.com/oncotarget 30552 Oncotarget estrogens, mediating tissue homeostasis, and protection BREAST CANCER against proliferative signals and can lead to breast atrophy. Sufficient androgen concentrations prevent the formation Breast cancer is the malignant growth of cells in the of breasts, even in genetic females, in certain disorders breast tissue, most frequently the epithelium of the duct such as adrenal tumors. The balance of estrogens and or lobule. During their lifetime, 10% of women will be androgens thus determine the future of the breast in any diagnosed with breast cancer. Many breast cancers are individual, and uncontrolled estrogen signaling is the steroid hormone dependent, and estrogen and androgen most widely accepted risk factor for breast cancer [1]. signaling have been shown to be the primary sex steroid The primary site of estrogen production in premenopausal hormones involved in regulating tumor growth and women is the ovaries, while most androgens are progression, with 70-80% of all breast cancers expressing synthesized in the adrenal glands [2]. In postmenopausal estrogen receptor (ER)α [10, 11] and 60-80% expressing women, the ovarian production of estrogens is greatly the androgen receptor (AR) [12, 13]. Estrogen signaling diminished, and adrenal androgens and sulfated estrogens by ERα in breast cancer cells results in proliferation become the primary circulating steroids. As a result of this and survival signals while suppressing the expression shift, the primary source of active estrogen in any tissue of antiproliferative and apoptotic targets [14, 15]. becomes the product of local conversion. This conversion Additionally, there is a second form of ER, known as in the breast tissue is primarily mediated by a number of ERβ (or ERβ1), which has growth inhibitory properties in enzymes, including aromatase, steroid sulfatase (STS) and breast cancer and can bind to ERα, forming heterodimers 17β-hydroxysteroid dehydrogenase (HSD17B) (Figure 1) which have reduced transcription potential [15]. Further, [3-9]. The relative expression of the different enzymes, ERβ splice variants ERβ2, ERβ3, ERβ4, and ERβ5, have combined with the availability of substrates, mediates the reduced ligand binding capacity, and function through balance and thus the final effect of the sex steroids in the heterodimer formation with ERβ1 or ERα, modulating local tissue. their activity and function. This topic is further discussed by Haldosen et al., and Sareddy et al., [16, 17]. The primary form of ER in healthy breast and most breast Figure 1: Schematic representation of the enzymatic conversion of sex steroids in breast tissue. DHEA = dehydroepiandrosterone. DHEA-S = dehydroepiandrosterone-sulfate. DHT = dihydrotestosterone. E1 = estrone. E2 = estradiol. E1-S = estrone–sulfate. E2-S = estradiol-sulfate. HSD3B1 = hydroxysteroid 3 beta-1. HSD17B = hydroxysteroid 17-beta dehydrogenase. STS = steroid sulfatase. SRD5A1 & 2 = steroid 5 alpha-reductase 1 and 2. www.impactjournals.com/oncotarget 30553 Oncotarget cancers is ERα, and as a result, most estrogen signaling is HSD17B1 AND 2 mediated through ERα signaling in breast cancer [15, 18]. Androgens, on the other hand, signal through AR. In ERα- HSD17B1 was the first type of HSD17B enzyme positive tissues, such as healthy breast and ERα-positive discovered, the gene HSD17B1 is localized to 17q11-q21 breast cancer, androgens are reported to be primarily anti- and encodes a 6 exon protein composed of 328 amino proliferative and are associated with improved outcome acids with a molecular mass of 34.95 kDa. The enzyme [19-23]. The role of androgens in ERα-negative disease is is expressed in the cytoplasm [6]. HSD17B1 is active as more controversial, showing either improved or worsened a homodimer composed of two subunits. The enzyme patient outcome when expressed. This discrepancy likely catalyzes reactions that increase the estrogenic activity of depends on confounding factors such as the presence of its ligands. The primary role of HSD17B1 is to mediate AR splice variants, V-7 in particular [24, 25], the presence the reduction of E1 to E2, and HSD17B1 has been of HER2 [26], the presence of FOXA1 [27], variations in shown to be the most active enzyme in regards to E2 the grade of the cohorts studied, and differing AR protein production [39]. HSD17B1 also catalyzes the reduction cut-off values [23, 28, 29]. In ERα-negative disease, of Dehydroepiandrosterone (DHEA) to androstenediol, clinical trials evaluating the effect of antiandrogens in which has reduced androgenic and increased estrogenic AR-positive patients are showing promising results activity [44, 45]. More recently, it has also been shown from treatment with antiandrogens bicalutamide and to metabolize DHT into 3β-diol and 3α-diol [46], both enzalutamide [30]. This review will focus on the HSD17B of which have much lower affinity for AR and increased family, which modulates 17β-hydroxysteroid activity affinity for ERβ and to some degree ERα compared to through reduction or oxidation of the carbon at the 17th DHT [47-49]. Maintenance of low DHT concentration position, and whose expression levels are frequently in the breast tissue is important for ERα-positive breast altered in breast cancer [6, 31-34]. cancer since increased DHT concentrations will result in inhibition of proliferation [50, 51]. HSD17B1 is primarily HSD17BS expressed in the placenta and ovary [6], but it is also expressed at lower levels in breast epithelium [35, 36]. The HSD17B family was first reported in the HSD17B2 is localized to 16q24.1-q24.2 and encodes 50’s when enzymes mediating conversation of 17β- a 6 exon protein composed of 387 amino acids with a hydroxysteroids (androgens and estrogens) in the placenta molecular mass of 42.785 kDa. The enzyme contains an were discovered [34]. In the 90’s the first members of the endoplasmatic
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