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Wegman, Pia
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Publications (10 of 10) Show all publications
Province, M. A., Goetz, M. P., Brauch, H., Flockhare, D. A., Hebert, J. M., Whaley, R., . . . Klein, T. E. (2014). CYP2D6 Genotype and Adjuvant Tamoxifen: Meta-Analysis of Heterogeneous Study Populations. Clinical Pharmacology and Therapeutics, 95(2), 216-227
Open this publication in new window or tab >>CYP2D6 Genotype and Adjuvant Tamoxifen: Meta-Analysis of Heterogeneous Study Populations
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2014 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 95, no 2, p. 216-227Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
New York, USA: Nature Publishing Group, 2014
National Category
Medical and Health Sciences Pharmacology and Toxicology
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-33895 (URN)10.1038/clpt.2013.186 (DOI)000330151100026 ()24060820 (PubMedID)2-s2.0-84893732936 (Scopus ID)
Note

Funding Agencies:

National Institutes of Health (National Institute of General Medical Sciences)

National Institutes of Health (National Cancer Institute)

National Institutes of Health (National Institute of Child Health and Human Development)

Breast Cancer Research (Scotland)  

Tayside Tissue Bank  

California Breast Cancer Research Program 

Cancer Research UK  

Deutsches Krebsforschungszentrum, Heidelberg, Germany  

Robert Bosch Foundation, Stuttgart, Germany  

Marie Curie Initial Training Network "FightingDrugFailure" 

GrantStichting Emmanuel van der Schueren (scientific partner of the Vlaamse Liga tegen Kanker)  

National Project for Personalized Genomic Medicine, Ministry for Health & Welfare, Republic of Korea 

Deutsche Forschungsgemeinschaft, Germany 

Available from: 2014-02-24 Created: 2014-02-24 Last updated: 2018-08-27Bibliographically approved
Göthlin Eremo, A., Wegman, P., Stål, O., Nordenskjöld, B., Fornander, T. & Wingren, S. (2013). Wwox expression may predict benefit from adjuvant tamoxifen in randomized breast cancer patients. Oncology Reports, 29(4), 1467-1474
Open this publication in new window or tab >>Wwox expression may predict benefit from adjuvant tamoxifen in randomized breast cancer patients
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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
Gao, L., Tu, Y., Wegman [Palmebäck-Wegman], P., Wingren, S. & Eriksson, L. A. (2011). A mechanistic hypothesis for the cytochrome P450-catalyzed cis-trans isomerization of 4-hydroxytamoxifen: an unusual redox reaction. Journal of Chemical Information and Modeling, 51(9), 2293-2301
Open this publication in new window or tab >>A mechanistic hypothesis for the cytochrome P450-catalyzed cis-trans isomerization of 4-hydroxytamoxifen: an unusual redox reaction
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2011 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 51, no 9, p. 2293-2301Article in journal (Refereed) Published
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.

National Category
Chemical Sciences Biomedical Laboratory Science/Technology
Research subject
Chemistry; Biomedicine
Identifiers
urn:nbn:se:oru:diva-20857 (URN)10.1021/ci2001082 (DOI)000295114700026 ()
Available from: 2012-01-11 Created: 2012-01-11 Last updated: 2018-02-14Bibliographically approved
Gao, L., Tu, Y., Wegman [Palmebäck-Wegman], P., Wingren, S. & Eriksson, L. A. (2011). Conformational enantiomerization and estrogen receptor alpha binding of anti-cancer drug tamoxifen and its derivatives. Journal of Chemical Information and Modeling, 51(2), 306-314
Open this publication in new window or tab >>Conformational enantiomerization and estrogen receptor alpha binding of anti-cancer drug tamoxifen and its derivatives
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2011 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 51, no 2, p. 306-314Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2011
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-17124 (URN)10.1021/ci100401t (DOI)000287685700012 ()21194224 (PubMedID)2-s2.0-79952139350 (Scopus ID)
Available from: 2011-09-05 Created: 2011-09-02 Last updated: 2017-12-08Bibliographically approved
Wegman, P., Göthlin Eremo, A., Lindlöf, A., Karlsson, M. G., Stål, O. & Wingren, S. (2011). Expression of the forkhead transcription factor FOXL2 correlates with good prognosis in breast cancer patients treated with tamoxifen. International Journal of Oncology, 38(4), 1145-1151
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
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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
Wegman [Palmebäck-Wegman], P., Ahlin, C. & Sorbe, B. (2011). Genetic alterations in the K-ras gene influence the prognosis in patients with cervical cancer treated by radiotherapy. International Journal of Gynecological Cancer, 21(1), 86-91
Open this publication in new window or tab >>Genetic alterations in the K-ras gene influence the prognosis in patients with cervical cancer treated by radiotherapy
2011 (English)In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 21, no 1, p. 86-91Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2011
Keywords
Cervical cancer, K-Ras, Mutation analysis, Prognostic factors
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-17165 (URN)10.1097/IGC.0b013e3182049924 (DOI)000285582500014 ()21330833 (PubMedID)2-s2.0-79951491860 (Scopus ID)
Available from: 2011-09-05 Created: 2011-09-02 Last updated: 2017-12-08Bibliographically approved
Wegman [Palmebäck-Wegman], P., Marcus, N. J., Malakkaran [Lindqvist], B. P. & Wingren, S. (2009). Biological significance of allele specific loss of the p53 gene in breast carcinomas. Breast Cancer Research and Treatment, 118(1), 15-20
Open this publication in new window or tab >>Biological significance of allele specific loss of the p53 gene in breast carcinomas
2009 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 118, no 1, p. 15-20Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Berlin: Springer Berlin/Heidelberg, 2009
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-7265 (URN)10.1007/s10549-008-0212-1 (DOI)000270737800003 ()18853251 (PubMedID)2-s2.0-70349925975 (Scopus ID)
Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2017-12-13Bibliographically approved
Lång, A., Palmebäck Wegman, P. & Wingren, S. (2009). The significance of MDM2 SNP309 and p53 Arg72Pro in young women with breast cancer. Oncology Reports, 22(3), 575-579
Open this publication in new window or tab >>The significance of MDM2 SNP309 and p53 Arg72Pro in young women with breast cancer
2009 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 22, no 3, p. 575-579Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Athens, Greece: Spandidos Publications, 2009
National Category
Cell and Molecular Biology
Research subject
Genetics
Identifiers
urn:nbn:se:oru:diva-8592 (URN)10.3892/or_00000474 (DOI)000268734600020 ()19639206 (PubMedID)2-s2.0-70349316753 (Scopus ID)
Available from: 2009-11-17 Created: 2009-11-17 Last updated: 2018-01-12Bibliographically approved
Licznerska, B. E., Wegman [Palmebäck-Wegman], P., Nordenskjöld, B. & Wingren, S. (2008). In situ levels of oestrogen producing enzymes and its prognostic significance in postmenopausal breast cancer patients. Breast Cancer Research and Treatment, 112(1), 15-23
Open this publication in new window or tab >>In situ levels of oestrogen producing enzymes and its prognostic significance in postmenopausal breast cancer patients
2008 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 112, no 1, p. 15-23Article in journal (Refereed) Published
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. 

Place, publisher, year, edition, pages
Berlin: Springer, 2008
Keywords
breast cancer
National Category
Medical and Health Sciences Cancer and Oncology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-7263 (URN)10.1007/s10549-007-9819-x (DOI)
Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2017-12-13Bibliographically approved
Tina, E., Malakkaran [Lindqvist ], B. P., Gabrielson, M., Lubovac, Z., Karlsson, M. G., Stål, O., . . . Wingren, S. A novel finding: SLC25A43 a solute carrier protein that is implicated in HER2 positive breast cancer.
Open this publication in new window or tab >>A novel finding: SLC25A43 a solute carrier protein that is implicated in HER2 positive breast cancer
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-10471 (URN)
Available from: 2010-04-26 Created: 2010-04-23 Last updated: 2017-10-18Bibliographically approved
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