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  • 1. Gabrielson, Marike
    et al.
    Göthlin Eremo, Anna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tina, Elisabet
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Karlsson, Elin
    Jakobsson, Frida
    Stål, Olle
    Wingren, Sten
    Regulation of cell proliferation and recurrence-free survival in HER2-positive breast cancer through SLC25A43 and p27Manuscript (preprint) (Other academic)
  • 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 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.

  • 3.
    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.

  • 4.
    Göthlin Eremo, Anna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tina, Elisabet
    Örebro University Hospital, Örebro, Sweden.
    Kruse, Robert
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Örebro University Hospital, Örebro, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Wegman, Pia
    Linköping University Hospital, Linköping, Sweden.
    Repsilber, Dirk
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Montgomery, Scott
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Public Health, University College London, UK .
    Sollie, Tomas
    Örebro University Hospital, Örebro, Sweden.
    Wingren, Sten
    Örebro University, School of Medicine, Örebro University, Sweden.
    Gene expression profiles in breast tumors from tamoxifen treated patients with and without distant recurrenceManuscript (preprint) (Other academic)
  • 5.
    Göthlin Eremo, Anna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tina, Elisabet
    Örebro University Hospital.
    Wegman, Pia
    Linköping University Hospital.
    Stål, Olle
    Linköping University.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fornander, Tommy
    Karolinska University Hospital, Karolinska Institute; Regional Cancer Center Stockholm-Gotland,.
    Wingren, Sten
    Örebro University, School of Medicine, Örebro University, Sweden.
    HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifenManuscript (preprint) (Other (popular science, discussion, etc.))
  • 6.
    Göthlin Eremo, Anna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Tina, Elisabet
    Örebro University Hospital. Clinical Research Centre, Örebro University Hospital, Örebro, Sweden.
    Wegman, Pia
    Department of Clinical Genetics, University Hospital, Linköping, Sweden.
    Stål, Olle
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Fransén, Karin
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fornander, Tommy
    Department of Oncology, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden; Regional Cancer Center Stockholm-Gotland, Stockholm, Sweden.
    Wingren, Sten
    Örebro University, School of Medicine, Örebro University, Sweden.
    HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen2015In: International Journal of Oncology, ISSN 1019-6439, Vol. 47, no 4, p. 1311-1320Article in journal (Refereed)
    Abstract [en]

    The human epidermal growth factor receptor (HER) 4 is a relative of HER2 and has been associated to endocrine breast cancer and prediction of tamoxifen response. In addition to PI3K/Akt and MAPK pathway activation, ligand binding to HER4 triggers proteolytic cleavage and release of an intracellular receptor domain (4ICD) with signaling properties. The aim of the present study was to analyze HER4 protein expression and intracellular localization in breast cancer tissue from patients randomized to treatment with or without adjuvant tamoxifen. To investigate HER4 expression and localization in response to estradiol (E2) and 4-hydroxytamoxifen (4-OHT) exposure, we also performed in vitro studies. Cytoplasmic, nuclear and membrane expression of HER4 protein was evaluated by immunohistochemical staining in tumor tissue from 912 breast cancer patients. Three different breast epithelia cancer cell lines were exposed to E2 and 4-OHT and mRNA expression was analyzed using qPCR. Further, nuclear and cytoplasmic proteins were separated and analyzed with western blotting. We found an association between nuclear HER4 protein expression and ER-positivity (P=0.004). Furthermore, significant association was found between cytoplasmic HER4 and ER-negativity (P<0.0005), PgR-negativity (P<0.0005), tumor size >20 mm (P=0.001) and HER2-negativity (P=0.008). However, no overall significance of HER4 on recurrence-free survival was found. After E2 exposure, HER4 mRNA and protein expression had decreased in two cell lines in vitro yet no changes in nuclear or cytoplasmic protein fractions were seen. In conclusion, nuclear HER4 seem to be co-located with ER, however, we did not find support for overall HER4 expression in independently predicting response of tamoxifen treatment. The possible influence of separate isoforms was not tested and future studies may further evaluate HER4 significance.

  • 7.
    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.

  • 8.
    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. 

  • 9.
    Lindqvist, Breezy Malakkaran
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Farkas, Sanja A.
    Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Wingren, Sten
    Örebro University, School of Medicine, Örebro University, Sweden.
    Nilsson, Torbjörn K.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    DNA methylation pattern of the SLC25A43 gene in breast cancer2012In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 7, no 3, p. 300-306Article in journal (Refereed)
    Abstract [en]

    Solute carrier family 25A member 43 (SLC25A43) gene is a putative tumor suppressor gene that undergoes loss of heterozygosity (LOH) in human epidermal growth factor receptor 2 (HER2) positive breast cancer. Also, knockdown of SLC25A43 in cell lines influences cell turnover and metabolism. Absence of mutations in this gene in breast cancers prompted us to study methylation as an alternate mechanism for gene inactivation of this X encoded gene. Quantification of CpG site methylation using pyrosequencing was performed upstream of the SLC25A43 gene and at its 5' end in a cohort of breast tumor tissues (n = 80, HER2 positive or negative) with different SLC25A43 gene deletion status. Compared with control tissue, cancer tissues had lower levels of methylation at the 5' and 3' shores of the gene. Cancer tissues with no deletion in the SLC25A43 gene (Del(-)) had higher methylation in the CpG island (CGI) of the gene than cancers carrying the deletion (Del(+)). Methylation in the CGI of the SLC25A43 gene was negatively correlated with age at diagnosis. In HER2 positive breast cancer, ER negativity and lymph node positivity was associated with higher methylation in the CGI and in the adjacent shores of this gene. Our results suggest that methylation in the CGI of the SLC25A43 gene could be an alternate mechanism of gene silencing in the absence of LOH. Also, associations between site-specific methylation and clinicopathological parameters suggest that epigenetic changes in SLC25A43 gene could be of importance in breast carcinogenesis.

  • 10.
    Lindqvist, Breezy Malakkaran
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Gyamfi, Jones
    Jakobsson, Frida
    Department of Oncology, Örebro University Hospital, SE-70185 Örebro, Sweden.
    Tina, Elisabet
    Clinical Research Centre, Örebro University Hospital, SE-70185 Örebro, Sweden.
    Wingren, Sten
    Örebro University, School of Medicine, Örebro University, Sweden.
    Cytoplasmic pFOXO3a expression is associated with sentinel node metastasis in HER2-positive breast cancerManuscript (preprint) (Other academic)
    Abstract [en]

    Introduction: Breast cancers with human epidermal growth factor receptor (HER) 2 gene amplification or protein overexpression (HER2+ breast cancer) is associated with poor prognosis. Activated HER2 receptors dimerise and activate the oncokinase Akt; which phosphorylate the tumour suppressor protein Forkhead box O3a (FOXO3a), repressing its transcriptional activity. Oncogenic FOXG1 can act as a transcriptional repressor for genes which are transcriptionally activated by FOXOs and phosphorylation of FOXG1 via Akt causes its nuclear export in differentiated cells. To better understand the AKT/FOXO3a/FOXG1 connection and their clinical relevance, we investigated the expression and localisation of pAkt, pFOXO3a and FOXG1 in HER2+ breast cancer.

    Methods: Immunohistochemical analysis was performed to determine the expression and localisation of pAkt, pFOXO3a and FOXG1 on tissue microarray constructs from HER2+ primary breast tumours (n=91) and their relation to clinic pathological parameters were analysed.

    Results: Nuclear expression of pAkt was found to be correlated to nuclear (p<0.001) as well as cytoplasmic expression of pFOXO3a (p = 0.006), while cytoplasmic expression of pAkt was found to be correlated to cytoplasmic expression of pFOXO3a (p<0.001). Nuclear expression of pFOXO3a was inversely correlated to cytoplasmic expression of FOXG1 (p=0.003). Cytoplasmic expression of pFOXO3a was found to be associated with sentinel node metastasis (p=0.011), while cytoplasmic FOXG1 expression was correlated to negative progesterone receptor status (p=0.008).

    Conclusion: Our results suggest that the expression and localisation of pAkt and pFOXO3a is interconnected, while the expression of FOXG1 is connected to pFOXO3a. Our findings indicate the biological value of expression as well as localisation of these proteins in HER2+ breast cancer.

  • 11.
    Lindqvist, Breezy Malakkaran
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Wingren, Sten
    Örebro University, School of Medicine, Örebro University, Sweden.
    Motlagh, Parviz B.
    Department of Medical Biosciences/Clinical Chemistry, Umeå University, Umeå, Sweden.
    Nilsson, Torbjorn K.
    Department of Medical Biosciences/Clinical Chemistry, Umeå University, Umeå, Sweden.
    Whole genome DNA methylation signature of HER2-positive breast cancer2014In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 9, no 8, p. 1149-1162Article in journal (Refereed)
    Abstract [en]

    In order to obtain a comprehensive DNA methylation signature of HER2-positive breast cancer (HER2+ breast cancer), we performed a genome-wide methylation analysis on 17 HER2+ breast cancer and compared with ten normal breast tissue samples using the Illumina Infinium HumanMethylation450 BeadChip (450K). In HER2+ breast cancer, we found altered DNA methylation in genes involved in multicellular development, differentiation and transcription. Within these genes, we observed an overrepresentation of homeobox family genes, including several genes that have not been previously reported in relation to cancer (DBX1, NKX2-6, SIX6). Other affected genes included several belonging to the PI3K and Wnt signaling pathways. Notably, HER2, AKT3, HK1, and PFKP, genes for which altered methylation has not been previously reported, were also identified in this analysis. In total, we report 69 candidate biomarker genes with maximum differential methylation in HER2+ breast cancer. External validation of gene expression in a selected group of these genes (n = 13) revealed lowered mean gene expression in HER2+ breast cancer. We analyzed DNA methylation in six top candidate genes (AKR1B1, INA, FOXC2, NEUROD1, CDKL2, IRF4) using EpiTect Methyl II Custom PCR Array and confirmed the 450K array findings. Future clinical studies focusing on these genes, as well as on homeobox-containing genes and HER2, AKT3, HK1, and PFKP, are warranted which could provide further insights into the biology of HER2+ breast cancer.

  • 12.
    Lindqvist, Breezy Malakkaran
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Wingren, Sten
    Örebro University, School of Medicine, Örebro University, Sweden.
    Nilsson, Torbjörn
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Whole genome DNA methylation signature of HER2-positive breast cancerManuscript (preprint) (Other academic)
    Abstract [en]

    With the aim of obtaining a more comprehensive epigenetic signature in HER2-positive breast cancer (HER2+ breast cancer), we performed a genome-wide methylation analysis on 17 HER2+ breast cancer and compared to 10 normal breast tissue samples using the Illumina Infinium HumanMethylation450 BeadChip that interrogates >485,000 CpG loci per sample. Our findings show that altered DNA methylation, more specifically hypermethylation occur at CpG islands in HER2+ breast cancer affecting genes involved in multicellular development, differentiation and transcription, and was overrepresented by the homeobox family of genes, including those which have not been previously reported in relation to cancer (DBX1, NKX2- 6, SIX6). Alteration in methylation was also found to affect genes of the PI3K and the Wnt signalling pathways in HER2+ breast cancer. Notably among them are HER2, AKT3, HK1 and PFKP, in which altered methylation has not been previously reported. We have identified 73 candidate biomarker genes in HER2+ breast cancer and external validation of gene expression in a selected group of these genes (n=13) revealed lowered mean gene expression in HER2+ breast cancer. Future clinical studies focusing on these candidate biomarker genes as well as homeobox-containing genes and HER2, AKT3, HK1 and PFKP are warranted which could provide further insights to the biology of HER2+ breast cancer.

  • 13.
    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.

  • 14. Löf-Ohlin, Zarah M.
    et al.
    Sorbe, Bengt
    Wingren, Sten
    Örebro University, School of Health and Medical Sciences.
    Nilsson, Torbjörn K.
    Örebro University, School of Health and Medical Sciences.
    Hypermethylation of promoter regions of the APC1A and p16(INK4a) genes in relation to prognosis and tumor characteristics in cervical cancer patients2011In: International Journal of Oncology, ISSN 1019-6439, Vol. 39, no 3, p. 683-688Article in journal (Refereed)
    Abstract [en]

    Hypermethylation of the O(6)-MGMT, p14(ARF), p16(INK4a), RASSFIA and APC1A genes are unfavourable prognostic markers in colorectal cancer (CRC). We hypothesized that they could be related to prognosis also in cervical cancer. Methylation was studied in DNA extracts from surgical specimens of cancer tissue by novel pyrosequencing methods. In 109 patients (90 squamous cell carcinomas, 19 adenocarcinomas), we found that hypermethylation of the APC1A gene promoter occurred in 8.3% of patients, and of p16(INK4a) in 1.8%. APC1A hypermethylation was significantly related to more advanced FIGO stage of the tumor (P=0.013), larger tumor diameter (P=0.049) and distant recurrence-free survival (P=0.0007), but not with locoregional recurrence rate, age, HPV status, DNA ploidy, tumor grade or malignancy grading score. We conclude that methylation of the APC1A promoter in cervical cancer, as diagnosed by pyrosequencing, is significantly related to major biological characteristics of the tumor, and may be a new predictor of poor prognosis in cervical cancer.

  • 15.
    Ohlin, Andreas
    et al.
    Department of Paediatrics, Örebro University Hospital, Örebro, Sweden.
    Bäckman, Anders
    Clinical Research Centre, Örebro University Hospital, Örebro, Sweden.
    Söderquist, Bo
    Department of Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Wingren, Sten
    Örebro University, School of Health and Medical Sciences.
    Björkqvist, Maria
    Örebro University, School of Health and Medical Sciences. Department of Paediatrics, Örebro University Hospital, Örebro, Sweden.
    Rapid typing of neonatal Staphylococcus epidermidis isolates using polymerase chain reaction for repeat regions in surface protein genes2010In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 29, no 6, p. 699-704Article in journal (Refereed)
    Abstract [en]

    Staphylococcus epidermidis is a significant pathogen in neonatal sepsis and other nosocomial infections. For further investigations of the colonisation patterns and invasive pathways, typing methods that are applicable on large populations of bacterial isolates are warranted. In the present study, a genotyping method based on polymerase chain reaction (PCR) for the repeat regions of four genes (sdrG, sdrF, aap and sesE) that encode for bacterial surface proteins was developed and applied to a sample of well-characterised neonatal blood isolates of S. epidermidis (n = 49). The PCR products were visualised on agarose gel (sdrG, sdrF and sesE) or by fragment analysis (aap). The discriminatory index (D-index) for genotyping of the different genes was compared to genotyping by pulsed-field gel electrophoresis (PFGE). The highest D-index for the PCR-based typing methods was found for the combination of sdrF, sdrG and aap (D-index 0.94), whereas the optimal two-gene combination (sdrF and aap) resulted in a D-index of 0.92. We conclude that the described method can be used for the genotyping of large populations of S. epidermidis isolates with a sufficient discriminatory capacity, and we suggest that the combination of sdrF and aap is the most suitable to use.

  • 16.
    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.

  • 17.
    Tina, Elisabet
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Clinical Research Centre, Örebro University Hospital, Örebro, Sweden.
    Lindqvist, Breezy Malakkaran
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Gabrielson, Marike
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Lubovac, Zelmina
    School of Life Sciences, University of Skövde, Skövde, Sweden.
    Wegman, Pia
    School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Wingren, Sten
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    The mitochondrial transporter SLC25A43 is frequently deleted and may influence cell proliferation in HER2-positive breast tumors2012In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, no 1, article id 350Article in journal (Refereed)
    Abstract [en]

    Background: Overexpression of the human epidermal growth factor receptor (HER) 2 is associated with poor prognosis and shortened survival in breast cancer patients. HER2 is a potent activator of several signaling pathways that support cell survival, proliferation and metabolism. In HER2-positive breast cancer there are most likely unexplored proteins that act directly or indirectly downstream of well established pathways and take part in tumor development and treatment response.

    Methods: In order to identify novel copy number variations (CNVs) in HER2-positive breast cancer whole-genome single nucleotide polymorphism (SNP) arrays were used. A PCR-based loss of heterozygosis (LOH) assay was conducted to verify presence of deletion in HER2-positive breast cancer cases but also in HER2 negative breast cancers, cervical cancers and lung cancers. Screening for mutations was performed using single-strand conformation polymorphism (SSCP) followed by PCR sequencing. Protein expression was evaluated with immunohistochemistry (IHC).

    Results: A common deletion at chromosome Xq24 was found in 80% of the cases. This locus harbors the gene solute carrier (SLC) family 25A member 43 (SLC25A43) encoding for a mitochondrial transport protein. The LOH assay revealed presence of SLC25A43 deletion in HER2-positive (48%), HER2-negative (9%), cervical (42%) and lung (67%) cancers. HER2-positive tumors with negative or low SLC25A43 protein expression had significantly lower S-phase fraction compared to tumors with medium or high expression (P = 0.024).

    Conclusions: We have found deletion in the SLC25A43 gene to be a common event in HER2-positive breast cancer as well as in other cancers. In addition, the SLC25A43 protein expression was shown to be related to S-phase fraction in HER2-positive breast cancer. Our results indicate a possible role of SLC25A43 in HER2-positive breast cancer and support the hypothesis of altered mitochondrial function in cancer.

  • 18.
    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)
  • 19.
    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.

  • 20.
    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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