title: A new polymorphism in the coding region of exon four in HSD17B2 in relation to risk of sporadic and hereditary breast cancer.
abstract: In situ synthesis of oestrogens is of great importance in the development and progression of breast cancer. 17beta-hydroxysteroid dehydrogenase (17HSD) type 2 catalyses oxidation from oestradiol to oestrone, and thereby protects the breast epithelial cells from oestradiol. Low expression of 17HSD type 2 has been associated with decreased survival in breast cancer, but no studies have investigated the mechanism behind the low expression. The 17HSD type 2 gene (HSD17B2) was screened for mutations with Single Stranded Conformation Polymorphism (SSCP)-DNA sequencing in 59 sporadic breast cancer cases, 19 hereditary breast cancer cases and seven breast cancer cell lines. DNA samples from 226 healthy individuals were used to identify if changes were previously unknown polymorphisms. No mutation was detected and therefore mutations in HSD17B2 do not explain why some breast tumours exhibit low 17HSD type 2 expression. However, a previously unknown polymorphism was found in exon four (Met226Val). Using molecular modelling, we found that the substituted residue is located at the outer part of the steroid binding site, probably causing minor alterations in the substrate binding. We further studied if the polymorphism contributes to breast cancer susceptibility in a larger material, but did not find an increased risk in the group of 317 sporadic breast cancer patients, 188 breast cancer patients with two close relatives with breast cancer or 122 hereditary breast cancer patients, compared to the healthy control group. We suggest that the detected polymorphism does not contribute to a higher risk of developing breast cancer.
authors.affiliation: Department of Biomedicine and Surgery, Linköping University, 581 85, Linköping, Sweden. agnja@ibk.liu.se
authors.forename: Agneta
authors.initials: A
authors.lastname: Jansson
authors.forename: Jonas
authors.initials: J
authors.lastname: Carlsson
authors.forename: Anette
authors.initials: A
authors.lastname: Olsson
authors.forename: Petter
authors.initials: P
authors.lastname: Storm
authors.forename: Sara
authors.initials: S
authors.lastname: Margolin
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gunnarsson
authors.forename: Marie
authors.initials: M
authors.lastname: Stenmark-Askmalm
authors.forename: Annika
authors.initials: A
authors.lastname: Lindblom
authors.forename: Bengt
authors.initials: B
authors.lastname: Persson
authors.forename: Olle
authors.initials: O
authors.lastname: Stål
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D004960:Estradiol Dehydrogenases / Q000737:chemistry / Q000235:genetics*; D005091:Exons; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D008958:Models, Molecular; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D011487:Protein Conformation; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human