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p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
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2006 (English)In: Pharmacogenetics and Genomics, ISSN 1744-6872, Vol. 16, no 5, 347-351 p.Article in journal (Refereed) Published
Abstract [en]

Background: Adjuvant therapy of breast cancer patients reduces the risk of recurrence and mortality, although, a substantial proportion of patients acquire resistance and relapse in the disease. Predictors of therapeutic response are therefore important to avoid both therapy resistance and the side effects of inefficient regimes. The p53 protein is a key determinant to induce either growth arrest or apoptosis in response to cytotoxic stress.

 

Methods: In the search for predictive markers of cancer therapy we investigated a common Arg72/Pro72 polymorphism in the p53 gene, which has been shown to influence the apoptotic potential. Using PCR and RFLP we genotyped 220 breast cancer patients randomized to radiotherapy versus chemotherapy and tamoxifen versus no tamoxifen.

 

Results: Oestrogen-receptor positive patients possessing at least one Pro72 allele had better distant recurrence-free survival when randomized to tamoxifen compared to those who were not (P=0.0033), as also demonstrated by the significantly decreased hazard ratio (HR=0.28, 95% CI 0.12–0.65). Among patients homozygous for the Arg72 genotype the outcome was approximately equal between tamoxifen treated and non-tamoxifen treated patients (P=0.65). When the calculated hazard ratios for the genotypes were compared by an interaction test a significant difference was found (P=0.0088).

 

Conclusion: The present report indicates that the codon 72 polymorphism in the p53 gene may be a predictor of tamoxifen response, suggesting that breast cancer patients lacking the Pro72 allele might be candidates for other therapies.

Place, publisher, year, edition, pages
2006. Vol. 16, no 5, 347-351 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-14537DOI: 10.1097/01.fpc.0000204997.84182.69OAI: oai:DiVA.org:liu-14537DiVA: diva2:23665
Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2013-03-28
In thesis
1. Studies of tamoxifen resistance in breast cancer
Open this publication in new window or tab >>Studies of tamoxifen resistance in breast cancer
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Oestrogen is one of the most important hormonal regulators and is known to play a key role in the development and growth of breast cancer. The majority of tumours have a hormone dependent growth, and this is indicated by the presence of oestrogen receptors (ERs). About two thirds of breast cancers occur after the menopause when the ovaries have ceased to produce oestrogen and despite the low levels of circulating oestrogen’s the tumour concentrations of oestrone, oestradiol and their sulfates have been shown to be significant. Patients with hormone dependent tumours are candidates for treatment with the anti-oestrogen tamoxifen, which acts by competing with oestrogen for binding to the ER thereby, diminish the transcription of oestrogen regulated genes. The drug is mainly metabolised by cytochrome P450 enzymes in the liver and to a lesser extent locally in the breast, where upon several produced metabolites have higher affinity for the ER than the mother substance. Patients treated with tamoxifen have in general a prolonged disease-free survival. Even if most patients respond well to tamoxifen about 30-50 % either fail to respond or become resistant by incompletely understood mechanisms. Therefore, the aim of this thesis was to investigate possible mechanisms responsible for tamoxifen resistance. In paper I and II we studied genetic variants of enzymes participating in the metabolism of tamoxifen and assessed whether these variants correlated to breast cancer prognosis and/or to the benefit of tamoxifen. The results indicate an influence of CYP2D6, CYP3A5, and SULT1A1 genotypes in tamoxifen response. Further, tamoxifen has shown to compete with oestrogen for the binding to ER. In paper III we measured the expression levels of enzymes involved in the local synthesis of oestrogens in order to see if they correlated to clinical outcome. The protein expression of stromal aromatase was shown to have a prognostic significance, especially in ER-positive patients. Finally, tamoxifen and its ER-active metabolites have shown to induce both cell cycle arrest and apoptosis and one central mediator in these processes is the tumour suppressor protein p53. The proapoptotic activity of p53 is dependent on a proline rich domain containing a common Pro-to-Arg polymorphism. In paper IV we examined the value of this genetic variant as a predictive marker for anti-cancer therapy and found that patients carrying the Pro-allele might be good responders of tamoxifen therapy. The present thesis further indicates the complexity of the mechanisms underlying tamoxifen resistance. In summary, genetic variants of metabolic enzymes, genetic variants in p53, as well as expression levels of enzymes involved in local oestrogen synthesis, may have influence on breast cancer prognosis and may be useful markers in the prediction of tamoxifen response.

Place, publisher, year, edition, pages
Institutionen för biomedicin och kirurgi, 2007. 68 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 987
Keyword
Breast cancer, tamoxifen, polymorphism, metabolic enzymes, oestrogen synthesis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-8943 (URN)978-91-85715-71-8 (ISBN)
Public defence
2007-03-30, Eken, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2009-05-11

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Wegman (Palmebäck), PiaStål, OlleStenmark Askmalm, MarieNordenskjöld, BoWingren, Sten

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