Abstract 5580: Wnt signaling as chemotherapy sensitivity marker of triple negative breast cancer (TNBC).

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: Triple negative breast cancer is characterized by an unfavorable prognosis. While patients do not benefit from endocrine or Her2 targeted therapies except chemotherapy, there is an increased response (pCR) to taxane-/anthracycline-containing therapy compared to other breast cancers. However, molecular determinants of chemotherapy specifically in TNBC remain largely unknown. Current research suggests an increased Wnt Pathway activity in TNBC while Wnt pathway activity has been shown to play an important role in breast cancer pathogenesis. Material and Methods: Differentially expressed genes in TN vs. non-TN breast cancers of patients treated with neoadjuvant taxane-/anthracycline-containing chemotherapy were identified and validated in an independent AffymetrixU133A gene chip dataset (Hess et al. 2006). Genes were tested for correlation with relapse-free survival, response to neoadjuvant chemotherapy and Ki67 expression. The effects of siRNA mediated knockdown of SFRP1 and treatment with small molecule XAV939 (specific inhibitor of Wnt signaling) were analyzed in TNBC cell lines MDA-MB 468, MDA-MB 231, HCC 1806 and luminal cell line MCF7 on chemo sensitivity. Results: Our list of over expressed genes in TNBC vs. non-TNBC contains several genes which are already discussed as potential markers for TNBC like αB-crystallin and transcription factor FOXC1. Furthermore, a few Wnt pathway associated genes (i.e. SFRP1, TCF7L1, TCF7L2, SOX10) occur in this list, which was validated in an independent dataset. While SFRP1 expression was not associated with relapse-free survival in TNBC, it was significantly correlated with a pCR. Importantly, no correlation to Ki67 expression could be demonstrated. mRNA knockdown of Wnt pathway inhibitor SFRP1 in two different TNBC cell lines (MDA-MB 468 and HCC 1806) resulted in an increased resistance to paclitaxel, doxorubicin and cisplatin. Treatment with Wnt inhibitor XAV939 resulted in TNBC cell lines MDA-MB 231, MDA-MB 468 and in luminal cell line MCF7 increased chemo sensitivity to paclitaxel and doxorubicin. Conclusion: We suggest Wnt Signaling and/or SFRP1 expression as a novel maker of chemotherapy sensitivity to taxane-, anthracycline and/or platinum-containing chemotherapy in TNBC in vitro that is independent of Ki67 expression. Citation Format: Carolin Huelsewig, Christof Bernemann, Christian Ruckert, Ludwig Kiesel, Lajos Pusztai, Cornelia Liedtke. Wnt signaling as chemotherapy sensitivity marker of triple negative breast cancer (TNBC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5580. doi:10.1158/1538-7445.AM2013-5580