Ellen K. Haraldsen

Bio: Ellen K. Haraldsen is an academic researcher from University of Oslo. The author has contributed to research in topics: Genotype & Aromatase. The author has an hindex of 3, co-authored 3 publications receiving 417 citations.

Genetic variants of CYP19 (aromatase) and breast cancer risk.

Abstract: The effect of a SNP in exon 10 of CYP19 on tumor mRNA levels and splice variants were studied and correlated with clinical parameters and risk of breast cancer. In the vast majority of breast cancers, the estrogen levels modulate the tumor growth and depend on the activity of CYP19. Patients (n=481) and controls (n=236) were genotyped by T-tracks in a single sequencing reaction (SSR). The frequency of TT genotypes was significantly higher in patients versus controls (P=0.007) particularly among those with stage III and IV disease (P=0.004) and with tumors larger than 5 cm (P=0.001). A significant association between presence of the T allele and the level of aromatase mRNA in the tumors was observed (P=0.018), as well as with a switch from adipose promoter to ovary promoter (P=0.004). Previously, we reported a rare polymorphic allele of CYP19 (repeat (TTTA)12) to be significantly more frequent in breast cancer patients than in controls. Here we describe another polymorphism, a C–T substitution in exon 10 of the CYP19 gene which is in strong linkage disequilibrium with the (TTTA)n polymorphism but with higher frequency of the variant allele. Our data suggest that the T-allele of the CYP19 gene is associated with a ‘high activity’ phenotype.

CYP17 and breast cancer risk: the polymorphism in the 5' flanking area of the gene does not influence binding to Sp-1.

Abstract: The ability of a motif of the CYP17 5' untranslated region, created by a polymorphic T to C substitution, to bind to the human transcription factor Sp-1 was investigated. No binding of any of the polymorphic alleles was observed in electromobility shift assay. No other sequence within +1 to +100 of each of the CYP17 alleles formed complex with the Sp-1 or enhanced binding to the polymorphic CACC box. Genotyping of 510 breast cancer patients and 201 controls revealed no difference in genotype frequencies. Age at onset, tumor grade, lymph node status and distant metastases, stage, and estrogen and progesterone receptor status were not associated with the CYP17 genotype.

Genetic variants of CYP19 (aromatase) and breast cancer risk

Abstract: The effect of a SNP in exon 10 of CYP19 on tumor mRNA levels and splice variants were studied and correlated with clinical parameters and risk of breast cancer. In the vast majority of breast cancers, the estrogen levels modulate the tumor growth and depend on the activity of CYP19. Patients (n=481) and controls (n=236) were genotyped by T-tracks in a single sequencing reaction (SSR). The frequency of TT genotypes was significantly higher in patients versus controls (P=0.007) particularly among those with stage III and IV disease (P=0.004) and with tumors larger than 5 cm (P=0.001). A significant association between presence of the T allele and the level of aromatase mRNA in the tumors was observed (P=0.018), as well as with a switch from adipose promoter to ovary promoter (P=0. 004). Previously, we reported a rare polymorphic allele of CYP19 (repeat (TTTA)12) to be significantly more frequent in breast cancer patients than in controls. Here we describe another polymorphism, a C - T substitution in exon 10 of the CYP19 gene which is in strong linkage disequilibrium with the (TTTA)n polymorphism but with higher frequency of the variant allele. Our data suggest that the T-allele of the CYP19 gene is associated with a 'high activity' phenotype. Oncogene (2000) 19, 1329 - 1333.

Polymorphisms Associated With Circulating Sex Hormone Levels in Postmenopausal Women

Abstract: Polymorphisms associated with circulating sex hormone levels in postmenopausal women Background: Reports suggest a relationship between circulating sex hormone levels and breast cancer risk, but genetic association studies have been inconclusive. We investigated the association between levels of sex hormones and single nucleotide polymorphisms (SNPs) in genes coding for the enzymes that regulate them. Methods: We assayed circulating levels of estradiol, testosterone, estrone, androstenedione, 17alpha- hydroxyprogesterone, and sex hormone-binding globulin (SHBG) in 1975 normal postmenopausal women. Fifteen SNPs in the CYP17, CYP19, EDH17B2, SHBG, COMT, and CYP1B1 genes were genotyped in these post menopausal women and in a breast cancer case-control study. Associations of genotypes with breast cancer risk were evaluated in the case-control study and with hormone levels in the postmenopausal women using multiple linear regression with assay batch, body mass index, parity, peri- or postmenopausal status, and age band as covariates. Results: CYP19 SNPs (rs10046 and [TCT]+/-) were associated with differences in estradiol level (P =.0006 and P =.0003, respectively) and the estradiol:testosterone ratio (P =.000001 and P =.002). SNP rs10046 explained 1.6% of the variance (r(2)) in the estradiol: testosterone ratio. SHBG SNPs (5' untranslated region [5'UTR] g-a and D356N) were associated with both SHBG levels (p< 10(-6) and P =.005) and the estradiol: SHBG ratio (P =.000008 and P =.01). These SNPs explained 2.4% and 0.6% of the variance in SHBG levels, respectively. SNPs in the other genes were not associated with differences in any hormone levels, and none were statistically significantly associated with breast cancer risk. Conclusion: Genetic variation in CYP19 and SHBG contributes to variance in circulating hormone levels between postmenopausal women, but low r(2) values may explain why these genes have given inconclusive results in breast cancer case- control studies. [J Natl Cancer Inst 2004;96:936-45]

Molecular epidemiology of sporadic breast cancer: The role of polymorphic genes involved in oestrogen biosynthesis and metabolism

Abstract: The major known risk factors for female breast cancer are associated with prolonged exposure to increased levels of oestrogen The predominant theory relates to effects of oestrogen on cell growth Enhanced cell proliferation, induced either by endogenous or exogenous oestrogens, increases the number of cell divisions and thereby the possibility for mutation However, current evidence also supports a role for oxidative metabolites, in particular catechol oestrogens, in the initiation of breast cancer As observed in drug and chemical metabolism, there is considerable interindividual variability (polymorphism) in the conjugation pathways of both oestrogen and catechol oestrogens These person-to-person differences, which are attributed to polymorphisms in the genes encoding for the respective enzymes, might define subpopulations of women with higher lifetime exposure to hormone-dependent growth promotion, or to cellular damage from particular oestrogens and/or oestrogen metabolites Such variation could explain a portion of the cancer susceptibility associated with reproductive effects and hormone exposure In this paper the potential role of polymorphic genes encoding for enzymes involved in oestrogen biosynthesis (CYP17, CYP19, and 17beta-HSD) and conversion of the oestrogen metabolites and their by-products (COMT, CYP1A1, CYP1B1, GSTM1, GSTM3, GSTP1, GSTT1 and MnSOD) in modulating individual susceptibility to breast cancer are reviewed Although some of these low-penetrance genes appeared as good candidates for risk factors in the etiology of sporadic breast cancer, better designed and considerably larger studies than the majority of the studies conducted so far are evidently needed before any firm conclusions can be drawn

Genes other than BRCA1 and BRCA2 involved in breast cancer susceptibility.

Abstract: This review focuses on genes other than the high penetrance genes BRCA1 and BRCA2 that are involved in breast cancer susceptibility. The goal of this review is the discovery of polymorphisms that are either associated with breast cancer or that are in strong linkage disequilibrium with breast cancer causing variants. An association with breast cancer at a 5% significance level was found for 13 polymorphisms in 10 genes described in more than one breast cancer study. Our data will help focus on the further analysis of genetic polymorphisms in populations of appropriate size, and especially on the combinations of such polymorphisms. This will facilitate determination of population attributable risks, understanding of gene-gene interactions, and improving estimates of genetic cancer risks.

The relationship between a polymorphism in CYP17 with plasma hormone levels and breast cancer.

Abstract: The A2 allele of CYP17 has been associated with polycystic ovarian syndrome, elevated levels of certain steroid hormones in premenopausal women, and increased breast cancer risk. We prospectively assessed the association between the A2 allele of CYP17 and breast cancer risk in a case-control study nested within the Nurses' Health Study cohort. We also evaluated associations between this CYP17 genotype and plasma steroid hormone levels among postmenopausal controls not using hormone replacement to assess the biological significance of this genetic variant. Women with the A2 allele were not at an increased risk of incident breast cancer [OR (odds ratio), 0.85; 95% CI (confidence interval), 0.65-1.12] or advanced breast cancer (OR, 0.84; 95% CI, 0.54-1.32). We did observe evidence that the inverse association of late age at menarche with breast cancer may be modified by the CYP17 A2 allele. The protective effect of later age at menarche was only observed among women without the A2 allele (A1/A1 genotype: for age at menarche > or =13 versus <13; OR, 0.57; 95% CI, 0.36-0.90; A1/A2 and A2/A2 genotypes: OR, 1.05; 95% CI, 0.76-1.45; P for interaction = 0.07). Among controls, we found women with the A2/A2 genotype to have elevated levels of estrone (+14.3%, P = 0.01), estradiol (+13.8%, P = 0.08), testosterone (+8.6%, P = 0.34), androstenedione (+17.1%, P = 0.06), dehydroepiandrosterone (+14.4%, P = 0.02), and dehydroepiandrosterone sulfate (+7.2%, P = 0.26) compared with women with the A1/A1 genotype. These data suggest that the A2 allele of CYP17 modifies endogenous hormone levels, but is not a strong independent risk factor for breast cancer.

Human Aromatase: Gene Resequencing and Functional Genomics

Abstract: Aromatase [cytochrome P450 19 (CYP19)] is a critical enzyme for estrogen biosynthesis, and aromatase inhibitors are of increasing importance in the treatment of breast cancer. We set out to identify and characterize genetic polymorphisms in the aromatase gene, CYP19 , as a step toward pharmacogenomic studies of aromatase inhibitors. Specifically, we “resequenced” all coding exons, all upstream untranslated exons plus their presumed core promoter regions, all exon-intron splice junctions, and a portion of the 3′-untranslated region of CYP19 using 240 DNA samples from four ethnic groups. Eighty-eight polymorphisms were identified, resulting in 44 haplotypes. Functional genomic studies were done with the four nonsynonymous coding single nucleotide polymorphisms (cSNP) that we observed, two of which were novel. Those cSNPs altered the following amino acids: Trp 39 Arg, Thr 201 Met, Arg 264 Cys, and Met 364 Thr. The Cys 264 , Thr 364 , and double variant Arg 39 Cys 264 allozymes showed significant decreases in levels of activity and immunoreactive protein when compared with the wild-type (WT) enzyme after transient expression in COS-1 cells. A slight decrease in protein level was also observed for the Arg 39 allozyme, whereas Met 201 displayed no significant changes in either activity or protein level when compared with the WT enzyme. There was also a 4-fold increase in apparent K m value for Thr 364 with androstenedione as substrate. Of the recombinant allozymes, only the double mutant (Arg 39 Cys 264 ) displayed a significant change from the WT enzyme in inhibitor constant for the aromatase inhibitors exemestane and letrozole. These observations indicate that genetic variation in CYP19 might contribute to variation in the pathophysiology of estrogen-dependent disease.