Disease relevance of HSD17B1

• The aim of this study was to investigate if HSD17B1 shows an altered gene copy number in breast cancer [1].
• The A-allele of HSD17B1 appears to confer higher risk for endometriosis [2].
• The present evidence indicates that pathways of estrogen metabolism are distinctly governed in prostate cancer cells depending on their endocrine status, being associated with a differential expression of mRNA for different 17 beta HSD enzymes [3].
• Human placental 17 beta-hydroxysteroid dehydrogenase is homologous to NodG protein of Rhizobium meliloti [4].
• In the endometrial carcinoma cell line, RL95-2, retinoic acid markedly increased the level of 17 beta-HSD type 2 messenger RNA in a time- and dose-dependent manner [5].

Psychiatry related information on HSD17B1

• Male pseudohermaphroditism due to 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) deficiency has a high prevalence within the Arab population of the Gaza strip and is characterised by marked virilization at puberty, leading in many cases to the spontaneous adoption of a male gender role [6].

High impact information on HSD17B1

• Defects in the conversion of androstenedione to testosterone in the fetal testes by the enzyme 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) give rise to genetic males with female external genitalia [7].
• That the progesterone receptor is functional in this tumor is evident from the induction of estradiol 17 beta-dehydrogenase activity upon progestin administration [8].
• The well-studied human placental cytosolic 17 beta-HSD (also referred to as estradiol dehydrogenase) preferentially catalyzes the reduction of estrone to estradiol-17 beta and the reduction of the C-20-ketone of progesterone to 20 alpha-dihydroprogesterone [9].
• The levels of 17 beta-HSD type 2 mRNA in secretory phase endometrium were approximately one-tenth that in villous trophoblast tissue from human placenta [9].
• This isoform of the enzyme has been referred to as 17 beta-HSD type 1 and localized to chromosome 17 [9].

Chemical compound and disease context of HSD17B1

• For estrogen receptor (ER)-positive patients who received adjuvant tamoxifen, amplification of HSD17B1 was related to decreased breast cancer survival (P=0.017), whereas amplification of ERRB2 was not [1].
• Association between endometriosis and genetic polymorphisms of the estradiol-synthesizing enzyme genes HSD17B1 and CYP19 [2].
• Since 17 beta-HSD is one of the most important enzymes involved in active steroid hormone formation, its inactivation could be a clinical approach to the treatment of hormono-dependent diseases like breast cancer [10].
• Human breast cancer tissues contain all the enzymes: estrone sulfatase, 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD), aromatase, involved in the last steps of E(2) bioformation in this tissue [11].
• In a study of the origin of estrogens in patients with breast cancer, the concentrations of estrogens and their androgen precursors, and aromatase and 17 beta-hydroxysteroid dehydrogenase (E2DH) activities were determined in normal glandular and cancerous breast tissue [12].

Biological context of HSD17B1

• However, reporter gene analysis revealed that the influence of Ro41 on the transcription of the HSD17B1 gene, which encodes 17HSD1, is considerably milder in JEG-3 cells, and it only additively enhanced the effect of at-RA [13].
• RESULTS: Individuals having at least one A-allele (A/G or A/A genotype) of HSD17B1 showed a significantly increased risk of endometriosis (A/G genotype: adjusted OR, 3.06; 95%CI 1.21-7.74; A/A genotype: adjusted OR, 3.02; 95%CI 1.08-8.43) [2].
• These data implicate the involvement of the cAMP-protein kinase signal transduction pathway in regulating lymphocyte expression of HSD17B1 [14].
• The human estradiol 17 beta-hydroxysteroid dehydrogenase II (17 beta-HSD II) gene has been assigned by somatic cell hybridization to chromosome 17q11-q21, near the region of assignment of the gene BRCA1, which is involved in hereditary breast-ovarian cancer [15].
• The nucleotide sequence of 17 beta-HSD II was completely determined in four unrelated individuals [15].

Anatomical context of HSD17B1

• Specifically, the high level of 17 beta HSD1 is clearly localized to follicles and corpora lutea indicating involvement in the synthesis of estradiol [16].
• The 17 beta-HSD type 2 is expressed to high levels in the liver, secretory endometrium and placenta [17].
• No mRNA for either 17 beta HSD1 or 17 beta HSD3 could be detected in any cell line [3].
• The protein contained an amino-terminal type II signal-anchor motif and a carboxyl-terminal endoplasmic reticulum retention motif, which suggested that 17 beta-HSD type 2 was associated with the membranes of the endoplasmic reticulum [18].
• Type 3 17 beta-HSD encodes the enzyme that catalyzes the conversion of A to T in the testis and also converts E1 to E2 [19].

Associations of HSD17B1 with chemical compounds

• Amplification of HSD17B1 might be an indicator of adverse prognosis among ER-positive patients, and possibly a mechanism for decreased benefit from tamoxifen treatment [1].
• Incubation with 10(-9) to 10(-7) M androstenedione or estradiol increased expression of HSD17B1, while testosterone decreased the expression of this gene [14].
• Other steroids, including dexamethasone, progesterone, and 6-hydroxypregnanolone, produced no effects on expression of either HSD17B1 or SRD5A1 [14].
• Detection of polymorphisms in the estradiol 17 beta-hydroxysteroid dehydrogenase II gene at the EDH17B2 locus on 17q11-q21 [15].
• Thus testosterone production within the human ovary, occurring under physiological conditions, arises from either the 17 beta HSD1 or an uncharacterized isozyme [16].

Physical interactions of HSD17B1

• CONCLUSIONS: The helices present in 17 beta-HSD that were not in the two previous short-chain dehydrogenase structures are located at one end of the substrate-binding cleft away from the catalytic triad [20].

Enzymatic interactions of HSD17B1

• In human placenta the enzyme complex aromatase catalyzes the conversion of androgens to estrogens and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) mediates the reversible interconversion of, e.g. estrone to estradiol [21].
• The cytosolic 17 beta-HSD I which exclusively catalyzes the interconversion of 17 beta-estradiol (E2) and estrone (E1) preferentially uses NADP+ and NADPH as cofactors [22].

Other interactions of HSD17B1

• In all, 32 tumors (14.5%) showed amplification of HSD17B1 and 21% were amplified for ERBB2 [1].
• Treatment with 10 or 50 microM forskolin resulted in a 20-60% reduction of expression for HSD17B1 (encoding 17beta-HSD I) in T and B lymphoid cell lines and peripheral blood mononuclear cells, although such a change was not observed in the expression of SRD5A1 (encoding 5alpha-reductase I) [14].
• The 17 beta-HSD3 gene is mutated in male pseudohermaphrodites with the genetic disease 17 beta-HSD deficiency [17].
• 17 beta-HSD5 was the predominant androgenic form of 17 beta-HSD expressed in human ovary [23].
• METHODS: We used primers specific for each type of 17 beta-HSD to identify quantitatively and directly sequence the polymerase chain reaction products of a human ovary library [23].

Analytical, diagnostic and therapeutic context of HSD17B1

• We used real-time PCR and examined 221 postmenopausal breast tumors for amplification of HSD17B1 and ERBB2 [1].
• In this study, we utilized Northern analysis and RT-PCR to examine transcripts for the three isozymes of 17 beta HSD [16].
• We examined both the subcutaneous abdominal and intra-abdominal (visceral) adipose tissue of women for expression of types 1, 2, and 3 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) using ribonuclease (RNase) protection assay and RT-PCR/Southern blotting [19].
• Haplotype analysis of the HSD17B1 gene and risk of breast cancer: a comprehensive approach to multicenter analyses of prospective cohort studies [24].
• We conducted a nested case-control study to evaluate whether polymorphisms in two genes involved in estrogen metabolism, CYP17 and HSD17B1, were useful in developing a breast cancer risk model that could help discriminate women who are at higher risk of breast cancer [25].

References