Insulin-like growth factor receptor polymorphism defines clinical outcome in estrogen receptor-positive breast cancer patients treated with tamoxifen

Winder, T, Giamas, G, Wilson, P M, Zhang, W, Yang, D, Bohanes, P, Ning, Y, Gerger, A, Stebbing, J and Lenz, H-J (2014) Insulin-like growth factor receptor polymorphism defines clinical outcome in estrogen receptor-positive breast cancer patients treated with tamoxifen. The Pharmacogenomics Journal, 14 (1). pp. 28-34. ISSN 1473-1150

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Abstract

Compelling evidence points to a key role for insulin-like growth factor 1 (IGF1) signaling in breast cancer development and progression. In addition, IGF1 receptor (IGF1R) expression has been correlated and functionally linked with estrogen receptor (ER) signaling. Recent translational studies support a cross talk between IGF1R and ERα at different levels and data suggest enhanced IGF1R signaling as a causative mechanism of tamoxifen (TAM) resistance. We tested whether functional germline variations in the IGF pathway are associated with clinical outcome in ER-positive primary invasive breast cancer patients, who were treated with surgery and adjuvant TAM. Tissue samples of 222 patients with ER+ primary invasive breast cancer, who had undergone surgery at Charing Cross Hospital, London, UK between 1981 and 2003, were analyzed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue samples and six functional IGF1 pathway polymorphisms were analyzed using direct DNA sequencing and PCR-restriction fragment length polymorphism. In multivariable analysis, patients with primary invasive breast cancer carrying IGF1R_rs2016347 G allele had a significantly increased risk of early tumor progression (hazard ratio (HR) 2.01; adjusted P=0.004) and death (HR 1.84; adjusted P=0.023) compared with patients carrying G/T or T/T, independent of established clinicopathological determinants. This association remained significant after adjusting for multiple testing. In addition, we were able to demonstrate that IRS1_rs1801123 and IGFBP3_rs2854744 were significantly associated with lymph node involvement and tumor size, respectively. We provide the first evidence for IGF1R_rs2016347 as an independent prognostic marker for ER+ breast cancer patients treated with TAM and support a rational for combined treatment strategies.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Depositing User: Georgios Giamas
Date Deposited: 07 Jul 2015 10:13
Last Modified: 07 Jul 2015 10:13
URI: http://sro.sussex.ac.uk/id/eprint/55201
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