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Studies of tamoxifen resistance in breast cancer
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
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 [en]
Breast cancer, tamoxifen, polymorphism, metabolic enzymes, oestrogen synthesis
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-8943ISBN: 978-91-85715-71-8 (print)OAI: oai:DiVA.org:liu-8943DiVA: diva2:23666
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
List of papers
1. Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients
Open this publication in new window or tab >>Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients
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2005 (English)In: Breast Cancer Research, ISSN 1465-5411(print), 1465-542X (online), Vol. 7, no 3, R284-R290 p.Article in journal (Refereed) Published
Abstract [en]

Background

Tamoxifen is widely used as endocrine therapy for oestrogen-receptor-positive breast cancer. However, many of these patients experience recurrence despite tamoxifen therapy by incompletely understood mechanisms. In the present report we propose that tamoxifen resistance may be due to differences in activity of metabolic enzymes as a result of genetic polymorphism. Cytochrome P450 2D6 (CYP2D6) and sulfotransferase 1A1 (SULT1A1) are polymorphic and are involved in the metabolism of tamoxifen. The CYP2D6*4 and SULT1A1*2 genotypes result in decreased enzyme activity. We therefore investigated the genotypes of CYP2D6 and SULT1A1 in 226 breast cancer patients participating in a trial of adjuvant tamoxifen treatment in order to validate the benefit from the therapy.

Methods

The patients were genotyped using PCR followed by cleavage with restriction enzymes.

Results

Carriers of the CYP2D6*4 allele demonstrated a decreased risk of recurrence when treated with tamoxifen (relative risk = 0.28, 95% confidence interval = 0.11–0.74, P = 0.0089). A similar pattern was seen among the SULT1A1*1 homozygotes (relative risk = 0.48, 95% confidence interval = 0.21–1.12, P = 0.074). The combination of CYP2D6*4 and/or SULT1A1*1/*1 genotypes comprised 60% of the patients and showed a 62% decreased risk of distant recurrence with tamoxifen (relative risk = 0.38, 95% confidence interval = 0.19–0.74, P = 0.0041).

Conclusion

The present study suggests that genotype of metabolic enzymes might be useful as a guide for adjuvant endocrine treatment of postmenopausal breast cancer patients. However, results are in contradiction to prior hypotheses and the present sample size is relatively small. Findings therefore need to be confirmed in a larger cohort.

Keyword
breast cancer, CYP2D6, polymorphism, SULT1A1, tamoxifen
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14534 (URN)10.1186/bcr993 (DOI)
Note
Original Publication: Pia Wegman, Linda Vainikka, Olle Stål, Bo Nordenskjöld, Lambert Skoog, Lars-Erik Rutqvist and Sten Wingren, Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients, 2005, Breast Cancer Research, (7), R284-290. http://dx.doi.org/10.1186/bcr993 Licensed by: CURRENT SCIENCE LTD Available from: 2009-02-22 Created: 2009-02-22 Last updated: 2009-06-08Bibliographically approved
2. Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal breast cancer patients
Open this publication in new window or tab >>Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal breast cancer patients
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2007 (English)In: Breast Cancer Research, ISSN 1465-5411(print) 1465-542X (online), Vol. 9, no 1, R7- p.Article in journal (Refereed) Published
Abstract [en]

Introduction

Tamoxifen therapy reduces the risk of recurrence and prolongs the survival of oestrogen-receptor-positive patients with breast cancer. Even if most patients benefit from tamoxifen, many breast tumours either fail to respond or become resistant. Because tamoxifen is extensively metabolised by polymorphic enzymes, one proposed mechanism underlying the resistance is altered metabolism. In the present study we investigated the prognostic and/or predictive value of functional polymorphisms in cytochrome P450 3A5 CYP3A5 (*3), CYP2D6 (*4), sulphotransferase 1A1 (SULT1A1; *2) and UDP-glucuronosyltransferase 2B15 (UGT2B15; *2) in tamoxifen-treated patients with breast cancer.

Methods

In all, 677 tamoxifen-treated postmenopausal patients with breast cancer, of whom 238 were randomised to either 2 or 5 years of tamoxifen, were genotyped by using PCR with restriction fragment length polymorphism or PCR with denaturing high-performance liquid chromatography.

Results

The prognostic evaluation performed in the total population revealed a significantly better disease-free survival in patients homozygous for CYP2D6*4. For CYP3A5, SULT1A1 and UGT2B15 no prognostic significance was observed. In the randomised group we found that for CYP3A5, homozygous carriers of the *3 allele tended to have an increased risk of recurrence when treated for 2 years with tamoxifen, although this was not statistically significant (hazard ratio (HR) = 2.84, 95% confidence interval (CI) = 0.68 to 11.99, P = 0.15). In the group randomised to 5 years' tamoxifen the survival pattern shifted towards a significantly improved recurrence-free survival (RFS) among CYP3A5*3-homozygous patients (HR = 0.20, 95% CI = 0.07 to 0.55, P = 0.002). No reliable differences could be seen between treatment duration and the genotypes of CYP2D6, SULT1A1 or UGT2B15. The significantly improved RFS with prolonged tamoxifen treatment in CYP3A5*3 homozygotes was also seen in a multivariate Cox model (HR = 0.13, CI = 0.02 to 0.86, P = 0.03), whereas no differences could be seen for CYP2D6, SULT1A1 and UGT2B15.

Conclusion

The metabolism of tamoxifen is complex and the mechanisms responsible for the resistance are unlikely to be explained by a single polymorphism; instead it is a combination of several mechanisms. However, the present data suggest that genetic variation in CYP3A5 may predict response to tamoxifen therapy.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14535 (URN)10.1186/bcr1640 (DOI)
Note
Original Publication: Pia Wegman, Sauli Elingarami, John Carstensen, Olle Stål, Bo Nordenskjöld and Sten Wingren, Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal breast cancer patients, 2007, Breast Cancer Research, (9), R7. http://dx.doi.org/10.1186/bcr1640 Licensed by: CURRENT SCIENCE LTD Available from: 2009-02-22 Created: 2009-02-22 Last updated: 2009-08-21Bibliographically approved
3. In situ levels of oestrogen producing enzymes and its prognostic significance in tamoxifen treated postmenopausal breast cancer patients
Open this publication in new window or tab >>In situ levels of oestrogen producing enzymes and its prognostic significance in tamoxifen treated postmenopausal breast cancer patients
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Manuscript (Other academic)
Identifiers
urn:nbn:se:liu:diva-14536 (URN)
Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2010-01-13
4. p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients
Open this publication in new window or tab >>p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients
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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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14537 (URN)10.1097/01.fpc.0000204997.84182.69 (DOI)
Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2013-03-28

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