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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.
    Göthlin Eremo, Anna
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Biological profiles of endocrine breast cancer2015Doctoral thesis, comprehensive summary (Other academic)
    List of papers
    1. Expression of the forkhead transcription factor FOXL2 correlates with good prognosis in breast cancer patients treated with tamoxifen
    Open this publication in new window or tab >>Expression of the forkhead transcription factor FOXL2 correlates with good prognosis in breast cancer patients treated with tamoxifen
    Show others...
    2011 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 38, no 4, p. 1145-1151Article in journal (Refereed) Published
    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.

    Keywords
    breast cancer, forkhead box L2, aromatase, tissue specific promoters, in silico
    National Category
    Cancer and Oncology
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-16840 (URN)10.3892/ijo.2011.923 (DOI)000288581100027 ()21271216 (PubMedID)2-s2.0-79952329924 (Scopus ID)
    Available from: 2011-09-02 Created: 2011-09-02 Last updated: 2018-05-03Bibliographically approved
    2. Wwox expression may predict benefit from adjuvant tamoxifen in randomized breast cancer patients
    Open this publication in new window or tab >>Wwox expression may predict benefit from adjuvant tamoxifen in randomized breast cancer patients
    Show others...
    2013 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 29, no 4, p. 1467-1474Article in journal (Refereed) Published
    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.

    Place, publisher, year, edition, pages
    Athens, Greece: Spandidos Publications, 2013
    Keywords
    Wwox, breast cancer, tamoxifen, randomized patients
    National Category
    Cancer and Oncology
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-41720 (URN)10.3892/or.2013.2261 (DOI)000316510600028 ()23381945 (PubMedID)2-s2.0-84874702740 (Scopus ID)
    Available from: 2015-01-15 Created: 2015-01-15 Last updated: 2018-05-23Bibliographically approved
    3. HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen
    Open this publication in new window or tab >>HER4 tumor expression in breast cancer patients randomized to treatment with or without tamoxifen
    Show others...
    (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
    Keywords
    Breast cancer, ErbB4, HER4, randomized patients, tamoxifen
    National Category
    Cancer and Oncology
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-44646 (URN)
    Available from: 2015-05-18 Created: 2015-05-18 Last updated: 2017-10-17Bibliographically approved
    4. Gene expression profiles in breast tumors from tamoxifen treated patients with and without distant recurrence
    Open this publication in new window or tab >>Gene expression profiles in breast tumors from tamoxifen treated patients with and without distant recurrence
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    Breast cancer, gene expression, microarray, tamoxifen
    National Category
    Cancer and Oncology
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-44650 (URN)
    Available from: 2015-05-18 Created: 2015-05-18 Last updated: 2017-10-17Bibliographically approved
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  • 3.
    Göthlin Eremo, Anna
    et al.
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Lagergren, Kajsa
    School of Medical Sciences, Faculty of Medicine and Health, Örebro university, Örebro, Sweden.
    Othman, Lana
    School of Medical Sciences, Faculty of Medicine and Health, Örebro university, Örebro, Sweden.
    Montgomery, Scott
    Örebro University, School of Medical Sciences. Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden; Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden.
    Andersson, Göran
    Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital Huddinge, Huddinge, Sweden.
    Tina, Elisabet
    Örebro University, School of Medical Sciences.
    Evaluation of SPP1/osteopontin expression as predictor of recurrence in tamoxifen treated breast cancer2020In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 10, no 1, article id 1451Article in journal (Refereed)
    Abstract [en]

    Breast cancer patients treated with tamoxifen may experience recurrence due to endocrine resistance, which highlights the need for additional predictive and prognostic biomarkers. The glyco-phosphoprotein osteopontin (OPN), encoded by the SPP1 gene, has previously shown to be associated with poor prognosis in breast cancer. However, studies on the predictive value of OPN are inconclusive. In the present study, we evaluated tissue SPP1 mRNA and OPN protein expression as markers of recurrence in estrogen receptor- positive (ER+) breast cancer tissue. Tamoxifen- treated patients with recurrence or non-recurrence were selected using a matched case-control design. SPP1 mRNA expression was analysed using qPCR (n = 100) and OPN protein by immunohistochemistry (n = 116) using different antibodies. Odds ratios were estimated with conditional logistic regression. The SPP1 expression increased the risk of recurrence with an odds ratio (OR) of 2.50 (95% confidence interval [CI]; 1.30-4.82), after adjustment for tumour grade, HER 2 status and other treatments to OR 3.62 (95% CI; 1.45-9.07). However, OPN protein expression was not associated with risk of recurrence or with SPP1-gene expression, suggesting SPP1 mRNA a stronger prognostic marker candidate compared to tumor tissue OPN protein.

  • 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.
    Paramel Varghese, Geena
    et al.
    Örebro University, School of Medical Sciences.
    Göthlin Eremo, Anna
    Örebro University Hospital, Örebro, Sweden.
    Ljungberg, Liza
    Örebro University, School of Medical Sciences.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences.
    Fransén, Karin
    Örebro University, School of Health Sciences.
    CARD8, a protein of innate immunity regulates the release of inflammatory cytokines in human endothelial cellsManuscript (preprint) (Other academic)
  • 9.
    Prosén, Sara
    et al.
    Örebro University, School of Medical Sciences. Department of Dermatology, Örebro University Hospital, Örebro, Sweden.
    Göthlin Eremo, Anna
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Clinical Research Laboratory, Örebro University Hospital, Örebro, Sweden.
    Tsegai, Alexander Duarte
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Lindberg, Magnus
    Örebro University, School of Medical Sciences. Department of Dermatology, Faculty of Health and Medical Sciences, Örebro University, Örebro, Sweden.
    Tina, Elisabet
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Clinical Research Laboratory, Örebro University Hospital, Örebro, Sweden.
    Decreased expression of the mitochondrial solute carrier SLC25A43 in basal cell carcinoma compared with healthy skin2017In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 14, no 2, p. 2218-2222Article in journal (Refereed)
    Abstract [en]

    Basal cell carcinoma is the most common type of cancer in fair-skinned individuals, and its incidence is rapidly increasing. The aim of the present study was to investigate the gene and protein expression of the mitochondrial solute carrier family 25 member 43 (SLC25A43) in basal cell carcinoma. SLC25A43 has previously been identified to be genetically altered and associated with cell proliferation in human epidermal growth factor receptor 2-positive breast cancer. However, the knowledge about SLC25A43 is limited, and its role in other cancers is unknown. The SLC25A43 gene and protein expression was analysed in 14 basal cell carcinomas and healthy skin samples from the same individuals by quantitative polymerase chain reaction and immunohistochemistry, respectively. The results demonstrated a significantly lower (>= 50%) SLC25A43 gene expression in all carcinomas compared with that in healthy skin. In addition, SLC25A43 protein expression was absent in >90% of all visual fields in the basal cell carcinomas, and the H-score was significantly lower in tumours compared with the adjacent epidermis. These results demonstrate that SLC25A43 expression is altered at the gene and protein levels in basal cell carcinoma. The underlying mechanisms and the clinical relevance of these data must be elucidated in additional experimental and clinical studies.

  • 10.
    Tina, Elisabet
    et al.
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Prosén, Sara
    Örebro University, School of Medical Sciences. Department of Dermatology, Örebro University hospital, Örebro, Sweden.
    Lennholm, S.
    School of Medical Sciences, Faculty of Medicine and Health, Örebro university, Örebro, Sweden.
    Gasparyan, G.
    School of Medical Sciences, Faculty of Medicine and Health, Örebro university, Örebro, Sweden.
    Lindberg, Magnus
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Dermatology, Örebro University hospital, Örebro, Sweden.
    Göthlin Eremo, Anna
    Örebro University, School of Medical Sciences. Department of Clinical Research Laboratory.
    Expression profile of the amino acid transporters SLC7A5, SLC7A7, SLC7A8 and the enzyme TDO2 in basal cell carcinoma2019In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 180, no 1, p. 130-140Article in journal (Refereed)
    Abstract [en]

    Background: The incidence of basal cell carcinoma (BCC) is increasing and the costs for care rising. Therefore, the need for simplified and cost-effective treatment choices is substantial. Aberrant signalling in several pathways, induced by ultraviolet radiation, is of importance in the development of BCC. Alterations in tumour metabolic activity are part of general carcinogenesis; however, these alterations are only partially recognized in skin cancer.

    Objectives: To study expression profiles in BCCs compared with individually matched nontumour skin, with a focus on finding differences associated with tumour metabolism.

    Materials and methods: Gene expression in biopsies from BCCs (n = 14) compared with biopsies from nontumour gluteal skin was analysed with microarrays (n = 4 + 4) and/or quantitative real-time polymerase chain reaction (qPCR, n = 14 + 14). Protein expression and localization was assessed using immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded BCC samples.

    Results: Microarray analysis revealed increased expression of the amino acid transporters SLC7A5, SLC7A7 and SLC7A8 as well as the cytosolic enzyme tryptophan 2,3-dioxygenase (TDO) 2 in BCC. Higher expression of SLC7A5 (P < 0.001), SLC7A8 (P < 0.001) and TDO2 (P = 0.002), but not SLC7A7 (P = 0.50), was confirmed by qPCR, and IHC demonstrated correlating tumour cell protein expression of SLC7A5 and SLC7A8. Protein expression of SLC7A7 was observed in the stratum granulosum, and TDO2 in immune cells.

    Conclusions: This study highlights the upregulation of SLC7A5, SLC7A8 and TDO2 in BCC compared with nontumour skin. Our findings imply that amino acid transporters may be further explored as potential targets for future medical treatment.

  • 11.
    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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