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Breast Cancer Research | Abstract | A randomised controlled phase ...

Open Access Research article

Rita D Brandao, Juergen Veeck, Koen K Van de Vijver, Patrick Lindsey, Bart de Vries, Catharine HMJ van Elssen, Marinus J Blok, Kristien Keymeulen, Torik Ayoubi, Hubert JM Smeets, Vivianne C Tjan-Heijnen and Pierre S Hupperets

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Breast Cancer Research 2013, 15:R29?doi:10.1186/bcr3409

Published: 8 April 2013

Abstract (provisional)

Introduction

Cyclooxygenase-2 (COX-2) is frequently over-expressed in primary breast cancer. In transgenic breast cancer models, over-expression of COX-2 leads to tumour formation while COX-2 inhibition exerts anti-tumour effects in breast cancer cell lines. To further determine the effect of COX-2 inhibition in primary breast cancer, here we aimed at identifying transcriptional changes in breast cancer tissues of patients treated with the selective COX-2 inhibitor celecoxib.

Methods

In a single-centre double-blinded phase II study, thirty-seven breast cancer patients were randomised to receive either pre-operative celecoxib (400 mg) twice daily for two to three weeks (n = 22) or a placebo likewise (n = 15). Gene expression in fresh-frozen pre-surgical biopsies (before treatment) and surgical excision specimens (after treatment) was profiled by using Affymetrix arrays. Differentially expressed genes and altered pathways were bioinformatically identified. Expression of selected genes was validated by quantitative PCR (qPCR). Immunohistochemical protein expression analyses of the proliferation marker Ki-67, the apoptosis marker cleaved caspase-3, and the neo-angiogenesis marker CD34 served to evaluate biological response.

Results

We identified 972 and 586 significantly up- and down-regulated genes, respectively, in celecoxib-treated specimens. Significant expression changes in six out of eight genes could be validated by qPCR. Pathway analyses revealed over-representation of deregulated genes in the networks of proliferation, cell cycle, extracellular matrix biology, and inflammatory immune response. The Ki-67 mean change relative to baseline was -29.1% (P = 0.019) and -8.2% (P = 0.384) in the treatment and control arm, respectively. Between treatment groups, the change in Ki-67 was statistically significant (P = 0.029). Cleaved caspase-3 and CD34 expression were not significantly different between the celecoxib-treated and placebo-treated group.

Conclusions

Short-term COX-2 inhibition by celecoxib induces transcriptional programs supporting an anti-tumour activity in primary breast cancer tissue. The impact on proliferation-associated genes is reflected by a reduction of Ki-67 positive cells. Therefore, COX-2 inhibition should be considered as treatment strategy for further clinical testing in primary breast cancer. Trial registration: ClinicalTrials.gov NCT01695226.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

Source: http://breast-cancer-research.com/content/15/2/R29

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