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Breast Cancer Research
Published in: Breast Cancer Research 6/2010

Open Access 01-12-2010 | Research article

Inactivation of FBXW7/hCDC4-β expression by promoter hypermethylation is associated with favorable prognosis in primary breast cancer

Authors: Shahab Akhoondi, Linda Lindström, Martin Widschwendter, Martin Corcoran, Jonas Bergh, Charles Spruck, Dan Grandér, Olle Sangfelt

Published in: Breast Cancer Research | Issue 6/2010

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Abstract

Introduction

Mutational inactivation of the FBXW7/hCDC4 tumor suppressor gene (TSG) is common in many cancer types, but infrequent in breast cancers. This study investigates the presence and impact of FBXW7/hCDC4 promoter methylation in breast cancer.

Methods

FBXW7/hCDC4-β expression and promoter methylation was assessed in 161 tumors from two independent breast cancer cohorts. Associations between methylation status and clinicopathologic characteristics were assessed by Fisher's exact test. Survival was analyzed using the Kaplan-Meier method in addition to modeling the risk by use of a multivariate proportional hazard (Cox) model adjusting for possible confounders of survival.

Results

Methylation of the promoter and loss of mRNA expression was found both in cell lines and primary tumors (43% and 51%, respectively). Using Cox modeling, a trend was found towards decreased hazard ratio (HR) for death in women with methylation of FBXW7/hCDC4-β in both cohorts (HR 0.53 (95% CI 0.23 to 1.23) and HR 0.50 (95% CI 0.23 to 1.08), respectively), despite an association between methylation and high-grade tumors (P = 0.017). Interestingly, in subgroups of patients whose tumors are p53 mutated or lymph-node positive, promoter methylation identified patients with significantly improved survival (P = 0.048 and P = 0.017, respectively).

Conclusions

We demonstrate an alternative mechanism for inactivation of the TSG FBXW7/hCDC4, namely promoter specific methylation. Importantly, in breast cancer, methylation of FBXW7/hCDC4-β is related to favorable prognosis despite its association with poorly differentiated tumors. Future work may define whether FBXW7/hCDC4 methylation is a biomarker of the response to chemotherapy and a target for epigenetic modulation therapy.
Appendix
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Metadata
Title
Inactivation of FBXW7/hCDC4-β expression by promoter hypermethylation is associated with favorable prognosis in primary breast cancer
Authors
Shahab Akhoondi
Linda Lindström
Martin Widschwendter
Martin Corcoran
Jonas Bergh
Charles Spruck
Dan Grandér
Olle Sangfelt
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 6/2010
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2788

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