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  • 1.
    Gao, Li
    et al.
    Örebro University, School of Science and Technology.
    Tu, Yaoquan
    Örebro University, School of Science and Technology.
    Wegman [Palmebäck-Wegman], Pia
    Örebro University, School of Health and Medical Sciences.
    Wingren, Sten
    Örebro University, School of Health and Medical Sciences.
    Eriksson, Leif A.
    A mechanistic hypothesis for the cytochrome P450-catalyzed cis-trans isomerization of 4-hydroxytamoxifen: an unusual redox reaction2011In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 51, no 9, p. 2293-2301Article in journal (Refereed)
    Abstract [en]

    We provide a detailed description of the cis-trans isomerization of 4-hydroxytamoxifen/endoxifen catalyzed by several isoforms from the cytochrome P450 (CYP) superfamily, including CYP1B1, CYP2B6, and CYP2C19. We show that the reactions mainly involve redox processes catalyzed by CYP, DFT calculation results strongly suggest that the isomerization occurs via a cationic intermediate. The cationic cis-isomer is more than 3 kcal/mol more stable than the trans form, resulting in an easier conversion from trans-to-cis than cis-to-trans. The cis-trans isomerization is a rarely reported CYP reaction and is ascribed to the lack of a second abstractable proton on the ethenyl group of the triarylvinyl class of substrates. The cationic intermediates thus formed instead of the stable dehydrogenation products allow for isomerization to occur. As a comparison, the reactions for the tamoxifen derivatives are compared to those of other substrates, 4-hydroxyacetanilide and raloxifene, for which the stable dehydrogenation products are formed.

  • 2.
    Gao, Li
    et al.
    Örebro University, School of Science and Technology.
    Tu, Yaoquan
    Örebro University, School of Science and Technology.
    Wegman [Palmebäck-Wegman], Pia
    Örebro University, School of Science and Technology.
    Wingren, Sten
    Örebro University, School of Science and Technology.
    Eriksson, Leif A.
    Örebro University, School of Science and Technology.
    Conformational enantiomerization and estrogen receptor alpha binding of anti-cancer drug tamoxifen and its derivatives2011In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 51, no 2, p. 306-314Article in journal (Refereed)
    Abstract [en]

    The anticancer drug tamoxifen (TAM) displays two chiral vinyl propeller structures, which interconvert so rapidly that the process is undetectable on the NMR time scale. In the present work, the enantiomerization processes were investigated with molecular modeling techniques. The threshold mechanisms probed at the different rings were shown to be identical, i.e., involving a synchronous three-ring flip, with a correlated rotation of the rings. In order to reveal the pharmacological profiles of the two chiral forms, we performed structural studies on the ligand binding domain of estrogen receptor alpha. (ER alpha LBD) and associated ligands. The enantiomers, with opposite torsional twist, were found to be discriminated by ER alpha. For TAM and its main metabolites, the effects of the stereoselectivity of ER alpha are overcome by the low energy cost for helical inversion between the two torsional enantiomers, estimated to be similar to 3 kcal/mol.

  • 3.
    Göthlin Eremo, Anna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital.
    Wegman, Pia
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Stål, Olle
    Department of Clinical and Experimental Medicine, Division of Oncology, Linköping University, Linköping, Sweden.
    Nordenskjöld, Bo
    Department of Clinical and Experimental Medicine, Division of Oncology, Linköping University, Linköping, Sweden.
    Fornander, Tommy
    Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Wingren, Sten
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Wwox expression may predict benefit from adjuvant tamoxifen in randomized breast cancer patients2013In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 29, no 4, p. 1467-1474Article in journal (Refereed)
    Abstract [en]

    Reduced or absent Wwox expression has recently been associated with tamoxifen resistance in breast cancer and has also been proposed as a candidate predictive marker for treatment. We aimed to investigate the correlation of Wwox expression with the outcome of tamoxifen treatment by examining tissues from 912 randomized breast cancer patients. Paraffin-embedded tissues from patient tumors were arranged on tissue microarray, and Wwox protein was stained using immunohistochemistry. After microscopic examination, the results were analyzed with Cox regression, Kaplan-Meier survival curves and the log-rank test. In the group of cases having a tumor absent for Wwox expression, there was no difference in recurrence-free survival between treated and untreated patients (P=0.81). For treated cases with a tumor expressing moderate or strong Wwox protein, recurrence-free survival was improved (P=0.001 and P=0.003, respectively). The test for interaction between Wwox and treatment response demonstrated a decreased risk of recurrence for treated patients with a moderate or strong Wwox expression (HR=0.31, 95% CI 0.10-0.98 and HR=0.28, 95% CI 0.08-0.97, respectively). Our results indicate that patients with high expression of Wwox may gain more benefit from treatment with tamoxifen.

  • 4.
    Licznerska, Barbara E.
    et al.
    Poznan´ University of Medical Sciences, Poznan.
    Wegman [Palmebäck-Wegman], Pia
    Örebro University, School of Health and Medical Sciences.
    Nordenskjöld, Bo
    Linköpings Universitet.
    Wingren, Sten
    Örebro University, School of Health and Medical Sciences.
    In situ levels of oestrogen producing enzymes and its prognostic significance in postmenopausal breast cancer patients2008In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 112, no 1, p. 15-23Article in journal (Refereed)
    Abstract [en]

    Background The risk of developing breast cancer is strongly correlated with the overall exposure to oestrogen and most tumours are more or less dependent on oestrogen for their growth. A great majority of breast cancers occur after menopause when the ovaries have ceased to be functional, yet breast tumours in postmenopausal women maintain high intratumoural oestrogen concentrations, primarily through enzymatic conversion of androgenic precursors. Patients with a hormone dependent tumour generally receive the anti-oestrogen tamoxifen that mediate its anti-tumour effect by competing with oestrogen for binding to the oestrogen-receptor (ER). We therefore propose that the levels of oestrogen producing enzymes may affect the prognosis in postmenopausal breast cancer patients treated with tamoxifen. Methods We measured the mRNA and protein levels of aromatase and sulfatase by real-time PCR (n = 161) and immunohistochemistry (n = 131) in postmenopausal women with breast cancer. Results A significant better recurrence-free survival was detected in patients with weak or high protein expression of stromal aromatase (P = 0.0008), as also demonstrated by a decreased relative risk (RR = 0.50, CI = 0.33–0.76, P = 0.003). When we combined patients with weak and high stromal aromatase and selected only ER-positive patients, the improved prognosis was even more evident (P = 0.0000) and was shown to be a significant prognostic factor in a multivariate Cox-model (HR = 0.15, CI = 0.06–0.39, P = 0.000). The mRNA expression of aromatase and sulfatase, as well as the protein expression of sulfatase revealed no prognostic significance. Conclusion Protein expression of stromal aromatase may serve as a significant prognostic marker in ER-positive patients. 

  • 5.
    Lång, Anna
    et al.
    Linköpings Universitet.
    Palmebäck Wegman, Pia
    Örebro University, School of Health and Medical Sciences.
    Wingren, Sten
    Örebro University, School of Health and Medical Sciences.
    The significance of MDM2 SNP309 and p53 Arg72Pro in young women with breast cancer2009In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 22, no 3, p. 575-579Article in journal (Refereed)
    Abstract [en]

    The p53 protein and its regulator MDM2 is central to tumorigenesis by directing cells to undergo cell cycle arrest and/or apoptosis in response to DNA damage or other stress signals. The genes encoding these proteins contain nucleotide variation (p53 codon 72, MDM2 SNP309) that influences cellular response. We examined the p53 codon 72 and MDM2 SNP309 to determine their implication with age of disease onset and risk of breast cancer in young women (≤36 years). No risk of breast cancer was observed for the genotypes of p53 and MDM2, however, a tendency (P=0.15) towards increased risk of early onset breast cancer was observed in carriers of two or more Pro and/or G alleles. We further calculated the influence on age at diagnosis. Cases were grouped according to the number of G and Pro alleles (0, 1, 2 or 3-4) and age at diagnosis. A significant trend towards decreased age at diagnosis with increased number of risk alleles was found (P=0.013). Our results suggest that p53 codon 72 and MDM2 SNP309 may be implicated in early onset breast cancer.

  • 6.
    Province, M. A.
    et al.
    Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis MO, USA.
    Goetz, M. P.
    Department of Oncology and Pharmacology, Mayo Clinic, Rochester MN, USA.
    Brauch, H.
    Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; Tübingen University, Tübingen, Germany.
    Flockhare, D. A.
    Division of Clinical Pharmacology, School of Medicine, Indiana University, Bloomington IN, USA.
    Hebert, J. M.
    Department of Genetics, School of Medicine, Stanford University, Stanford CA, USA.
    Whaley, R.
    Department of Genetics, School of Medicine, Stanford University, Stanford CA, USA.
    Suman, V. J.
    Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester MO, USA.
    Schroth, W.
    Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; Tübingen University, Tübingen, Germany.
    Winter, S.
    Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University, Tuebingen, Germany.
    Zembutsu, H.
    Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
    Mushiroda, T.
    Laboratory for Pharmacogenetics, RIKEN Center for Genomic Medicine, Yokohama, Japan.
    Newman, W. G.
    Centre for Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
    Lee, M-TM.
    Laboratory for International Alliance, RIKEN Center for Genomic Medicine, Yokohama, Japan.
    Ambrosone, C. B.
    Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo NY, USA.
    Beckmann, M. W.
    Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
    Choi, J-Y
    Department of Biomedical Science, Graduate School, Seoul National University, Seoul, Korea.
    Dieudonne, A-S
    Department of Oncology, Catholic University Leuven, Leuven, Belgium.
    Fasching, P. A.
    Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany; Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles CA, USA.
    Ferraldeschi, R.
    Centre for Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
    Gong, L.
    Department of Genetics, School of Medicine, Stanford University, Stanford CA, USA.
    Haschke-Becher, E.
    University Institute of Medical and Chemical Laboratory Diagnostics, Paracelsus Private Medical University, Salzburg, Austria.
    Howel, A.
    The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
    Jordan, L. B.
    Department of Pathology, Ninewells Hospital and Medical School, Dundee, UK.
    Hamann, U.
    Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
    Kiyotani, K.
    Laboratory for Pharmacogenetics, RIKEN Center for Genomic Medicine, Yokohama, Japan.
    Krippl, P.
    Medical University Graz, Graz, Austria.
    Lambrechts, D.
    Vesalius Research Center, VIB and Laboratory of Translational Genetics, Department of Oncology, Catholic University Leuven, Leuven, Belgium.
    Latif, A.
    Centre for Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
    Langsenlehner, U.
    Medical University Graz, Graz, Austria.
    Lorizio, W.
    Division of General Internal Medicine, Department of Medicine and Clinical Pharmacology and Experimental Therapeutics, and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco CA, USA.
    Neven, P.
    Department of Gynecology and Obstetrics, University Hospitals Leuven, Leuven, Belgium.
    Nguyen, A. T.
    Division of Clinical Pharmacology, School of Medicine, Indiana University, Bloomington IN, USA.
    Park, B-W.
    Department of Surgery, Yonsei University Health System, Seoul, Korea.
    Purdie, C. A.
    Department of Pathology, Ninewells Hospital and Medical School, Dundee, UK.
    Quinlan, P.
    Dundee Cancer Centre, Dundee, UK.
    Renner, W.
    Medical University Graz, Graz, Austria.
    Schmidt, M.
    Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University Tübingen, Tübingen, Germany; Department of Gynecology and Obstetrics, University of Mainz, Mainz, Germany.
    Schwab, M.
    Department of Clinical Pharmacology and Toxicology, University Hospital Tuebingen, Tuebingen, Germany.
    Shin, J-G
    Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, Korea; Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Korea.
    Stingl, J. C.
    Division of Research, Federal Institute for Drugs and Medical Devices, University of Bonn Medical Faculty, Bonn, Germany.
    Wegman, Pia
    Örebro University, School of Health and Medical Sciences.
    Wingren, Sten
    Örebro University, School of Medicine, Örebro University, Sweden.
    Wu, A. H. B.
    Department of Laboratory Medicine, University of California, San Francisco CA, USA.
    Ziv, E.
    Division of General Internal Medicine, Department of Medicine and Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco CA, USA.
    Zirpoli, G.
    Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo NY, USA.
    Thompson, A. M.
    Dundee Cancer Centre, Dundee, UK.
    Jordan, V. C.
    Department of Oncology, Georgetown University, Washington DC, USA.
    Nakamura, Y.
    Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
    Altman, R. B.
    Department of Genetics, School of Medicine, Stanford University, Stanford CA, USA; Department of Bioengineering, Stanford University, Stanford CA, USA.
    Ames, M. M.
    Department of Pharmacology, Mayo Clinic, Rochester MN, USA.
    Klein, T. E.
    Department of Genetics, School of Medicine, Stanford University, Stanford CA, USA.
    CYP2D6 Genotype and Adjuvant Tamoxifen: Meta-Analysis of Heterogeneous Study Populations2014In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 95, no 2, p. 216-227Article in journal (Refereed)
    Abstract [en]

    The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1), CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

  • 7.
    Tina, Elisabet
    et al.
    Örebro University, School of Health and Medical Sciences.
    Malakkaran [Lindqvist ], Breezy Paul
    Örebro University, School of Health and Medical Sciences.
    Gabrielson, Marike
    Örebro University, School of Health and Medical Sciences.
    Lubovac, Zelmina
    School of life sciences, University of Skövde, Sweden.
    Karlsson, Mats G.
    Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Stål, Olle
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden .
    Wegman, Pia
    Örebro University, School of Health and Medical Sciences.
    Wingren, Sten
    Örebro University, School of Health and Medical Sciences.
    A novel finding: SLC25A43 a solute carrier protein that is implicated in HER2 positive breast cancerManuscript (preprint) (Other academic)
  • 8.
    Wegman [Palmebäck-Wegman], Pia
    et al.
    Örebro University, School of Health and Medical Sciences.
    Ahlin, Cecilia
    Sorbe, Bengt
    Genetic alterations in the K-ras gene influence the prognosis in patients with cervical cancer treated by radiotherapy2011In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 21, no 1, p. 86-91Article in journal (Refereed)
    Abstract [en]

    Introduction: A high incidence of K-Ras mutations has been identified in a variety of human cancers, especially in codon 12, 13, and 61. Nevertheless, the presence of K-Ras mutations in cervical cancer remains controversial. The aim of this study was to investigate possible mutations in exon 1 and 2 of the K-Ras gene and to assess whether K-Ras mutation status had prognostic and predictive significance and were linked to clinicopathological parameters. Methods: Genomic DNA from 107 patients with cervical cancer, treated with radio-chemotherapy, were examined for mutations in the coding exons 1 and 2, including exon/intron borders of the K-Ras gene using single-stranded conformation polymorphism and sequence analyses. Results: K-Ras mutations were detected in 11 patients (10%). Seven tumors showed a mutation in codon 59, 3 tumors in codon 38, and 1 tumor in codon 13. In 6 of the cases with a mutation in codon 59, an additional alteration located in codon 65 was found. Patients with K-Ras mutations had significantly worse recurrence-free survival (P = 0.03), and an association between K-Ras status and distant metastases was also seen (P = 0.04). Conclusions: The present data indicate that K-Ras mutations are relatively uncommon in cervical cancer but associates with poorer prognosis, especially in the subset of squamous cell carcinomas. There is a need for new markers in cervical cancer to improve individual treatment, but whether K-Ras mutation status is a potential biomarker in this situation needs further investigations in larger tumor series and in more regions of the K-Ras gene.

  • 9.
    Wegman [Palmebäck-Wegman], Pia
    et al.
    Örebro University, School of Health and Medical Sciences.
    Marcus, Nashwan J.
    Linköpings Universitet.
    Malakkaran [Lindqvist], Breezy Paul
    Örebro University, School of Health and Medical Sciences.
    Wingren, Sten
    Örebro University, Department of Clinical Medicine.
    Biological significance of allele specific loss of the p53 gene in breast carcinomas2009In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 118, no 1, p. 15-20Article in journal (Refereed)
    Abstract [en]

    The p53 tumor suppressor gene has a central role in the defense against cancer, including breast cancer, and contains a polymorphic variant (Arg/Pro) at codon 72 that has been shown to have different biological properties regarding apoptosis and cell cycle arrest. Earlier studies have shown allele specific loss of heterozygosity (LOH) at this particular site and we aimed to investigate its biological relevance in codon 72 heterozygous breast cancer patients (i.e., survival and age of disease onset). 199 postmenopausal cases were analyzed for LOH using MegaBACE1000 and statistics was performed using Statistical Package for Social Sciences. LOH was found in totally 124 (62.3%) patients and the Pro allele (n = 103) was significantly more often deleted compared to the Arg allele (n = 21) (P = 0.001). Patients with LOH of the Arg allele were diagnosed at an earlier age (mean age 62.5 years) than those with loss of the Pro allele (mean age 69.2 years) (P = 0.011). LOH of the Arg allele was also associated with worse survival (P = 0.05). LOH in comparison to ROH correlated significantly with increased S-phase fraction. Tumor size, stage or number of positive lymph nodes was not related to LOH. Our results and earlier findings suggest a selective loss of the Pro allele during carcinogenesis that might confer a growth advantage for cancer cells. On the other hand, it appears to be more harmful for patients to loose the Arg allele since we found that loss of this allele was associated with earlier onset and worse prognosis.

  • 10.
    Wegman, Pia
    et al.
    Örebro University, School of Health and Medical Sciences.
    Göthlin Eremo, Anna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Lindlöf, Angelica
    University of Skövde, Skövde, Sweden.
    Karlsson, Mats G.
    Örebro University Hospital, Örebro, Sweden.
    Stål, Olle
    Linköping University, Linköping, Sweden.
    Wingren, Sten
    Örebro University, School of Health and Medical Sciences.
    Expression of the forkhead transcription factor FOXL2 correlates with good prognosis in breast cancer patients treated with tamoxifen2011In: International Journal of Oncology, ISSN 1019-6439, Vol. 38, no 4, p. 1145-1151Article in journal (Refereed)
    Abstract [en]

    Aromatase is an important enzyme in the local synthesis of oestrogens and its expression has been shown to be increased in breast cancer through the activation of multiple promoters. However, the mechanisms behind this are not yet fully understood. A novel candidate in this context is the transcription factor forkhead box L2 (FOXL2), which has been recognised to be co-expressed with aromatase and transcriptionally active promoter 11 in developing goat and chicken ovaries. We propose that FOXL2 could be involved in the increased expression of aromatase in breast cancer. We examined FOXL2 and its relation to aromatase in 132 postmenopausal breast cancer patients by immunohistochemistry. Using in silico analysis, we further searched for FOXL2 binding-elements in the aromatase gene promoters. The results demonstrate that FOXL2 is expressed in breast cancer and influences clinical outcome with improved recurrence-free survival in cases with nuclear expression. In a multivariate Cox model, nuclear FOXL2 was a significant prognostic factor in ER-positive patients treated with tamoxifen (HR=0.18, 95% confidence interval (CI)=0.04-0.81, P=0.03). Tumours expressing nuclear FOXL2 were also more likely positive for stromal and/or cytoplasmic aromatase (P=0.03 and P=0.008, respectively). In silico analyses revealed binding elements of FOXL2 in promoters 1.3, 11 and 17 of the aromatase gene of which promoter 1.7 was most significant. In conclusion, this is the first study to report that FOXL2 is expressed in breast cancer and correlates with aromatase as well as with clinical outcome. The results further strengthen a possible binding of FOXL2 to aromatase promoter 1.7. Nevertheless, whether FOXL2 is a direct activator of aromatase requires further investigation.

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