The key role of 17β-hydroxysteroid dehydrogenases in sex steroid biology

Labrie, Fernand; Luu‐The, Van; Lin, Sheng‐Xiang; Labrie, Claude; Simard, Jacques; Breton, R.; Bélanger, Alain

doi:10.1016/s0039-128x(96)00174-2

Cited by 440 publications

(276 citation statements)

References 59 publications

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“…This is also in agreement with the fact that breast cancer tissue possesses all the enzymes necessary for the bioformation of estradiol (Yue et al, 1998;Purohit et al, 2002). Among these enzymes are 17b-hydroxysteriod dehydrogenases (17b-HSD), which control the final step in the formation of androgens and estrogens (Labrie et al, 1997). The 17b-HSD type 1 enzyme uses NADPH as a cofactor and catalyzes the interconversion of the weak estrogen, estrone (E1), to the biologically more potent estradiol (E2).…”

Section: Introductionsupporting

confidence: 80%

Amplification of HSD17B1 and ERBB2 in primary breast cancer

et al. 2003

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Estrogens play a crucial role in the development of breast cancer. Estradiol can be produced in the breast tissue in situ, and one of the enzymes involved in this process is 17b-hydroxysteriod dehydrogenase (17b-HSD) type 1 that catalyzes the interconversion of estrone (E1) to the biologically more potent estradiol (E2). The gene coding for 17b-HSD type 1 (HSD17B1) is located at 17q12-21, close to the more studied ERBB2 and BRCA1. The aim of this study was to investigate if HSD17B1 shows an altered gene copy number in breast cancer. We used real-time PCR and examined 221 postmenopausal breast tumors for amplification of HSD17B1 and ERBB2. In all, 32 tumors (14.5%) showed amplification of HSD17B1 and 21% were amplified for ERBB2. Amplification of the two genes was correlated (P ¼ 0.00078) and in 14 tumors (44%) with amplification of HSD17B1, ERBB2 was co amplified. The patients with amplification in at least one of the genes had a significantly worse outcome than patients without (P ¼ 0.0059). For estrogen receptor (ER)-positive patients who received adjuvant tamoxifen, amplification of HSD17B1 was related to decreased breast cancer survival (P ¼ 0.017), whereas amplification of ERRB2 was not. Amplification of HSD17B1 might be an indicator of adverse prognosis among ER-positive patients, and possibly a mechanism for decreased benefit from tamoxifen treatment.

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Section: Introductionsupporting

confidence: 80%

Amplification of HSD17B1 and ERBB2 in primary breast cancer

et al. 2003

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“…preferentially acts as a reductase because of high cellular NADPH/NADP ϩ and NAD ϩ /NADH ratios. 22) Previously few ketosteroids were found as the substrates of DD1 and DD3 and the K m values for the substrates were determined only with DD3.…”

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confidence: 99%

Characterization of Two Isoforms of Mouse 3(17).ALPHA.-Hydroxysteroid Dehydrogenases of the Aldo-Keto Reductase Family

Ishikura

Usami

Nakajima

et al. 2004

Biological & Pharmaceutical Bulletin

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Mouse kidney contains two 3(17)a a-hydroxysteroid dehydrogenases (HSDs) that show essentially the same properties except for their isoelectric points. However, the structural differences and physiological roles of the two enzymes remain unknown. In this study, we have isolated cDNAs for the two 3(17)a a-HSDs from a total RNA sample of mouse kidney by reverse transcription-PCR. The identity of the cDNAs was confirmed by characterization of the recombinant enzymes that showed the same molecular weights, pI values, pH optima, substrate specificity and inhibitor sensitivity as those of the enzymes from mouse kidney. We also found that the recombinant enzymes reduce precursors of neuroactive progesterone derivatives, 5a a-dihydrotestoserone, deoxycorticosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate and estrone at low K m values of 0.3-2 m mM. The two enzymes belonged to the aldo-keto reductase (AKR) family, and their 323-amino acid sequences differed only by five amino acids. The sequences of the two isoforms are identical to those of proteins that are predicted to be encoded in a gene for AKR1C21 in the database of the mouse genome. However, the mRNAs for the two isoforms were expressed in mouse kidney and other tissues, in which their expression levels were different. The results indicate an important role of 3(17)a a-HSD in controlling the concentrations of various steroid hormones in the mouse tissues, and suggest the existence of two genes for the two isoforms of the enzyme.

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“…The 17-HSD enzyme complex controls the final step in the formation of all androgens and oestrogens, and thus plays a key role in regulating local hormone concentrations (reviewed in Labrie et al, 1997). To date, six distinct isoforms of 17-HSD, designated I-VI, have been identified and cloned.…”

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confidence: 99%

In vivo and in vitro expression of steroid-converting enzymes in human breast tumours: associations with interleukin-6

et al. 1999

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Summary Enzymes modulating local steroid availability play an important role in the progression of human breast cancer. These include isoforms of 17β-hydroxysteroid dehydrogenase (17-HSD), aromatase and steroid sulphatase (STS). The aim of this study was to investigate the expression, by reverse transcription polymerase chain reaction, of 17-HSD types I-IV, aromatase and steroid STS in a series of 51 human breast tumour biopsies and 22 primary cultures of epithelial and stromal cells derived from these tumours, giving a profile of the steroidregulating network for individual tumours. Correlations between enzyme expression profiles and expression of the interleukin (IL)-6 gene were also sought. All except one tumour expressed at least one isoform of 17-HSD, either alone or in combination with aromatase and STS. Expression of 17-HSD isoforms I-IV were observed in nine tumours. Of the 15 tumours which expressed three isoforms, a combination of 17-HSD II, III and IV was most common (6/15 samples). The majority of tumours (n = 17) expressed two isoforms of 17-HSD with combinations of 17-HSD II and IV predominant (7/17 samples). Eight tumours expressed a single isoform and of these, 17-HSD I was in the majority (5/8 samples). In primary epithelial cultures, enzyme expression was ranked: HSD I (86%) > STS (77%) > HSD II (59%) > HSD IV (50%) = aromatase (50%) > HSD III (32%). Incidence of enzyme expression was generally reduced in stromal cultures which were ranked: HSD I (68%) > STS (67%) > aromatase (48%) > HSD II (43%) > HSD IV (28%) > HSD III (19%). Expression of IL-6 was associated with tumours that expressed ≥ 3 steroid-converting enzymes. These tumours were of higher grade and tended to come from patients with family history of breast cancer. In conclusion, we propose that these enzymes work in tandem with cytokines thereby providing sufficient quantities of bioactive oestrogen from less active precursors which stimulates tumour growth.

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The key role of 17β-hydroxysteroid dehydrogenases in sex steroid biology

Cited by 440 publications

References 59 publications

Amplification of HSD17B1 and ERBB2 in primary breast cancer

Amplification of HSD17B1 and ERBB2 in primary breast cancer

Characterization of Two Isoforms of Mouse 3(17).ALPHA.-Hydroxysteroid Dehydrogenases of the Aldo-Keto Reductase Family

In vivo and in vitro expression of steroid-converting enzymes in human breast tumours: associations with interleukin-6

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