Secreted Frizzled Receptor Protein 1 (sFRP-1) as Both a Potential Novel Biomarker of Triple Negative Breast Cancer (TNBC), and Its Sensitivity Against Taxane/Anthracycline Containing Neoadjuvant Chemotherapy.

Abstract

Abstract Background: Patients with triple negative breast cancer (TNBC) carry an unfavorable prognosis despite an increased response to chemotherapy compared to other breast cancer subtypes. While tumor grade/proliferation is one major determinant of chemosensitivity in TNBC, we have recently suggested additional (molecular) features to have a significant impact as well.Material and Methods: Differential gene expression analysis was performed between TNBC (n=27) versus non-TNBC (n=106) using gene expression profiles (Affymetrix U133A) from breast cancers of patients treated with neoadjuvant taxane/anthracycline chemotherapy at MDACC (Hess et al. 2006). Differentially expressed genes were validated using profiles of 286 patients with breast cancer who did not receive systemic therapy (Wang et al. 2006). Genes were tested for (a) an association with relapse free survival, (b) an association with response to neoadjuvant chemotherapy and (c) correlation with Ki67 expression. siRNA knockdown experiments using triple negative and non-triple negative cell lines were carried out using both (a) a proliferation assay and (b) a chemosensitivity assay.Results: The secreted frizzled receptor protein 1 (sFRP-1), a member of the wnt-pathway, was identified as the top differentially overexpressed gene in TNBC (i.e. false discovery rate [FDR] < 0,0001) and successfully validated in the independent dataset. In TNBC, sFRP-1 expression showed no association with relapse-free survival, but significantly correlated with an increased sensitivity to neoadjuvant chemotherapy. Importantly, it did not correlate with expression of Ki67 in TNBC. siRNA-mediated knockdown of sFRP-1 expression intriple negative MDA-MB 468 breast cancer cell lines was associated with increased proliferation and most importantly decreased sensitivity to paclitaxel in vitro.Conclusion: We suggest sFRP-1 as a novel marker of (a) the triple negative breast cancer phenotype in general and (b) its chemosensitivity to taxane-containing chemotherapy independent of Ki67 expression. Preliminary siRNA-based cell culture experiments suggest sFRP-1 to play a causal role with regard to chemosensitivity of TNBC rather than solely constituting a novel marker thereof. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4047.