Abstract 920: Secreted frizzled related protein 1 (SFRP1) as potential regulator of chemotherapy response for patients with triple negative breast cancer (TNBC)

Abstract

Abstract Background: Triple negative breast cancer (TNBC) is associated with an unfavorable prognosis and increased response to chemotherapy. While proliferation rate and tumor grade are determining factors, we have recently suggested additional molecular structures to have significant impact. Based on differential gene expression analysis we identified SFRP1 (secreted frizzled related protein 1) to be a potential molecular marker for response to chemotherapy and potential prognostic marker. Methods: Differential gene expression analysis was performed between TNBC (n=27) versus non-TNBC (n=106) using AffymetrixU133A gene chips 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). SFRP1 knockdown experiments with the TNBC cell line MDA-MB 468 were performed via siRNA transfection and carried out using assays for proliferation, chemo- and radioresistance. Results: SFRP1 was identified as differentially overexpressed gene in TNBC and successfully validated in the independent dataset. Protein and mRNA quantification of SFRP1 (TNBC vs. non-TNBC cell lines) confirm that. While in TNBC, SFRP1 expression showed no association with recurrence-free survival, it is significantly correlated with an increased sensitivity to neoadjuvant chemotherapy. siRNA-mediated knockdown of SFRP1 expression in MDA-MB 468 was associated with increased G2-arrested cells and importantly increased resistance to paclitaxel, doxorubicin and cis-platinum. Furthermore, radioresistance of MDA-MB 468 cells was significantly increased after SFRP1 knockdown. Interestingly, sensitivity to salinomycin was slightly increased after SFRP1 knockdown. Salinomycin is known to kill cancer stem cells (Gupta et al. 2009). Additionally, cancerous characteristics (invasion and migration) were increased after SFRP1 knockdown while target gene expression analysis revealed an association between loss of SFRP1 and activation of mTOR/PI3K signaling. Conclusion: We suggest SFRP1 as a novel predictive marker of chemotherapy sensitivity to taxane, anthracycline and platinum-containing chemotherapy independent of Ki67 expression. Further on, we have shown the influence of SFRP1 on cancerous characteristics thus, suggesting SFRP1 as potential prognostic marker. Molecular role of SFRP1 may be the influence on enrichment of cancer stem cell population which are known to be resistant against chemotherapeutics and radiation and are usually slow proliferating. Interestingly, the mTOR/PI3K signaling might be activated via loss of SFRP1 which could display an opportunity for patients with TNBC resistant to current chemotherapeutics. Citation Format: Carolin Huelsewig, Christof Bernemann, Christian Ruckert, Ludwig Kiesel, Martin Goette, Achim Rody, Lajos Pusztai, Georg Hempel, Cornelia Liedtke. Secreted frizzled related protein 1 (SFRP1) as potential regulator of chemotherapy response for patients with triple negative breast cancer (TNBC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 920. doi:10.1158/1538-7445.AM2014-920