Abstract
17β-Hydroxysteroid dehydrogenase (17HSD) is one of the key enzymes in estrogen metabolism, catalyzing the reversible reaction between estradiol and the less active estrogen, estrone. The gene encoding this enzyme, EDH17B2, has been mapped to chromosome 17, region q12–q21, in the vicinity of BRCA1, an as yet unidentified gene that appears to be involved in familial breast cancer and in familial ovarian cancer. The possibility that EDH17B2 gene is the same as BRCA1 was tested by screening for mutations in the coding regions of EDH17B2, using a polymerase chain reaction/single-strand conformation polymorphism method. An A→G transition creating a new BstUI site at exon 6 was the only frequent sequence alteration found in the coding region of the gene. This mutation also led to an amino acid substitution of serine to glycine at position 312 (312S→312G) in the 17HSD protein. Since the nucleotide change was detected both in specimens from patients with familial or sporadic cancer and in control samples, and at similar rates, this mutation appears to be of a polymorphic nature. In addition, a rare polymorphism located at intron 5 was detected. This C→T substitution creates a BbvI site and is not thought to have any effect on 17HSD activity. The results indicate that there are no major alterations in the coding areas of EDH17B2 and thus studies testing the hypothesis that EDH17B2 may be the same as BRCA1 should be extended to the promoter and regulatory elements of EDH17B2.
Similar content being viewed by others
References
Black DM, Solomon E (1993) The search for the familial breast/ovarian cancer gene. Trends Genet 9:22–26
Chen EY, Seeburg PH (1985) Supercoil sequencing: a fast and simple method for sequencing DNA. DNA 4:165–170
Cullen KJ, Lippman ME (1989) Estrogen regulation of protein synthesis and cell growth in human breast cancer. Vitam Horm 45:127–172
Easton DF, Bishop DT, Ford D, Crockford GP, Breast Cancer Linkage Consortium (1993) Genetic analysis in familial breast and ovarian cancer: results in 214 families. Am J Hum Genet 52:678–701
Engel LL, Groman EV (1974) Human placental 17β-estradiol dehydrogenase: characterization and structural studies. Recent Prog Horm Res 30:139–169
Fournier S, Brihmat F, Durand JC, Sterkers N, Martin PM, Kuttenn F, Mauvais-Jarvis P (1985) Estradiol 17β-hydroxysteroid dehydrogenase, a marker of breast cancer hormone dependency. Cancer Res 45:2895–2899
Futreal PA, Söderkvist P, Marks JR, Iglehart JD, Cochran C, Barrett JC, Wiseman RW (1992) Detection of frequent allelic loss on proximal chromosome 17q in sporadic breast carcinoma using microsatellite length polymorphism. Cancer Res 52:2624–2627
Gompel A, Malet C, Spritzer P, Lalardrie JP, Kutten F, Mauvais-Jarvis P (1986) Progestin effect on cell proliferation and 17β-hydroxysteroid dehydrogenase activity in normal human breast cells in culture. J Clin Endocrinol Metab 63:1174–1180
Hall JM, Lee MK, Newmann B, Morrow JE, Anderson LA, Huey B, King M-C (1990) Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250:1684–1689
Hall JM, Friedman L, Guenther C, Lee MK, Weber JL, Black DM, King M-C (1992) Closing in on a breast cancer gene on chromosome 17q. Am J Hum Genet 50:1235–1242
Kamboh MI, Hamman RF, Ferrel RE (1992) Two common polymorphisms in the APO A-IV coding gene: their evolution and linkage disequilibrium. Genet Epidemiol 9:305–315
Langer LJ, Engel LL (1958) Human placental estradiol-17β dehydrogenase. I. Concentration, characterization and assay. J Biol Chem 233:583–588
Luu The V, Labrie C, Zhao HF, Couët J, Lachance Y, Simard J, Leblanc G, Côté J, Bérubé D, Gagné R, Labrie F (1989) Characterization of cDNAs for human estradiol 17β-dehydrogenase and assignment of the gene to chromosome 17: evidence of two mRNA species with distinct 5′-termini in human placenta. Mol Endocrinol 3:1301–1309
Luu The V, Labrie C, Simard J, Lachance Y, Zhao H-F, Couët J, Leblanc G, Labrie F (1990) Structure of two in tandem human 17β-hydroxysteroid dehydrogenase genes. Mol Endocrinol 4:268–275
Margaritte P, Bonaiti-Pellie C, King M-C, Clerget-Darpoux F (1992) Linkage of familial breast cancer to chromosome 17q21 may not be restricted to early-onset disease. Am J Hum Genet 50:1231–1234
Narod SA, Feunteun J, Lynch HT, Watson P, Conway T, Lynch J, Lenoir GM (1991) Familial breast-ovarian cancer locus on chromosome 17q12-q23. Lancet 338:82–83
Normand T, Narod S, Labrie F, Simard J (1993) Detection of polymorphisms in the estradiol 17B-hydroxysteroid dehydrogenase II gene at the EDH17B2 locus on 17q11-q21. Hum Mol Genet 2:479–483
Orita M, Suzuki Y, Sekiya T, Hayashi K (1989) Rapid and sensitive detection of point mutations and DNA polymorphism using the polymerase chain reaction. Genomics 5:874–879
Peltoketo H, Isomaa V, Mäentausta O, Vihko R (1988) Complete amino acid sequence of human placental 17β-hydroxysteroid dehydrogenase deduced from cDNA. FEBS Lett 239:73–77
Peltoketo H, Isomaa V, Vihko R (1992) Genomic organization and DNA sequences of human 17β-hydroxysteroid dehydrogenase genes and flanking regions. Localization of multiple Alu sequences and putative cis-acting elements. Eur J Biochem 209:459–466
Poutanen M, Isomaa V, Lento V-P, Vihko R (1992) Immunological analysis of 17β-hydroxysteroid dehydrogenase in benign and malignant human breast tissue. Int J Cancer 50:386–390
Prudhomme JF, Malet C, Gompel A, Lalardrie JP, Ochoa C, Bou A, Mauvais-Jarvis P, Kuttenn F (1984) 17β-Hydroxysteroid dehydrogenase activity in human breast epithelial cell and fibroblast cultures. Endocrinology 114:1483–1489
Sanger F, Nicklen S, Coulson AR (1977) DNA sequence with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467
Simard J, Feunteun J, Lenoir G, Tonin P, Normand T, Luu The V, Vivier A, Lasko D, Morgan K, Rouleau GA, Lynch H, Labrie F, Narod SA (1993) Genetic mapping of the breast-ovarian cancer syndrome to a small interval on chromosome 17q12–21:exclusion of candidate genes EDH17B2 and RARA. Hum Mol Genet 2:1193–1199
Smith SA, Easton DF, Evans DGR, Ponder BAJ (1992) Allele losses in the region 17q12–21 in familial breast and ovarian cancer involve the wild-type chromosome. Nature Genet 2:128–131
Smith SA, Easton DF, Ford D, Peto J, Anderson K, Averill D, Stratton M, Ponder M, Pye C, Ponder BAJ (1993) Genetic heterogeneity and localization of a familial breast-ovarian cancer gene on chromosome 17q12-q21. Am J Hum Genet 52:767–776
Solomon E, Ledbetter DH (1991) Report of the committee on the genetic constitution of chromosome 17. Cytogenet Cell Genet 58:686–738
Tabor S, Richardson CC (1987) DNA sequence analysis with modified bacteriophage T7 DNA polymerase. Proc Natl Acad Sci USA 84:4767–4771
Vandenplas S, Wiid I, Grobler-Rabie A, Brebner K, Ricketts M, Wallis G, Bester A, Boyd C, Mathew C (1984) Blot hybridization of genomic DNA. J Med Genet 21:164–172
Vihko R, Apter D (1989) Endogenous steroids in the pathophysiology of breast cancer. Crit Rev Oncol Hematol 9:1–16
Winqvist R, Peltoketo H, Isomaa V, Grzeschik K-H, Mannermaa A, Vihko R (1990) The gene for 17beta-hydroxysteroid dehydrogenase maps to human chromosome 17, bands q12–q21, and shows an RFLP with ScaI. Hum Genet 85:473–476
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Mannermaa, A., Peltoketo, H., Winqvist, R. et al. Human familial and sporadic breast cancer: analysis of the coding regions of the 17β-hydroxysteroid dehydrogenase 2 gene (EDH17B2) using a single-strand conformation polymorphism assay. Hum Genet 93, 319–324 (1994). https://doi.org/10.1007/BF00212030
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00212030