Received on April 11, 2006
Accepted on July 3, 2006

Cancer Diagnostics

Do the Survivin Splice Variants Modulate or Add to the Prognostic Value of Total Survivin in Breast Cancer?

¹ Department of Chemical Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
² Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
³ Department of Clinical Chemistry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
⁴ Department of Medical Oncology, Erasmus MC-Daniel den Hoed, Rotterdam, The Netherlands

^* To whom correspondence should be addressed. E-mail: p.span{at}ace.umcn.nl.

Background: A total of 4 additional splice variants (survivin-Ex3, survivin 2, survivin-2B, and survivin-3B) have been described of survivin [baculoviral IAP repeat-containing protein (BIRC-5), approved gene symbol BIRC5], which has been implicated in both inhibition of apoptosis and regulation in mitosis in many tumor types. In this study, we assessed whether the survivin splice variants modulate or add to the prognostic value of total survivin in breast cancer.

Methods: With quantitative reverse transcription-PCR, we measured mRNA concentrations of survivin and all variants in tumor tissue from 275 patients with breast cancer and associated with clinicopathologic characteristics and relapse-free survival.

Results: Total survivin, survivin-Ex3, and survivin 2 mRNA levels were associated with young age and ductal histology. Total survivin and survivin-Ex3 were highest in samples with advanced histological grade, whereas patients with 4-9 involved lymph nodes expressed less survivin-2B mRNA than those with 1-3 involved nodes. All variants were higher in steroid hormone receptor negative tumors. Total survivin, survivin 2, and survivin-3B were associated with poor relapse-free survival in univariate analyses. Survivin 2 and survivin-3B added to the prognostic value of total survivin in multivariate analyses. In addition, the prognostic value of total survivin was only evident in the presence of higher expression levels of these 2 variants.

Conclusions: All variants of survivin exhibited particular associations with clinicopathologic characteristics (age, histology, grade, and steroid hormone receptor status) of breast cancer patients. Survival analyses suggest a modulating role of survivin 2 and survivin-3B on the biological function of total survivin.