Abstract 3024: Elucidation of WNT signaling pathway players “sFRP-1” and “TCF7L2” as novel potential biomarkers of triple negative breast cancer

Abstract

Abstract Background: Triple negative breast cancer (TNBC) is characterized by an unfavorable prognosis. While patients do not benefit from endocrine or Her2 targeted therapies except chemotherapy, there is an increased propability of response to taxane-/anthracycline-containing therapy compared to other breast cancers. However, molecular determinants of chemotherapy sensitivity for patients with TNBC specifically remain largely unknown. The WNT signaling cascade has been shown to play an important role in breast cancer pathogenesis. Material and Methods: Differentially expressed genes in triple negative (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. Genes were tested for correlation with relapse-free survival, response to neoadjuvant chemotherapy and Ki67 expression. The effects of siRNA mediated knockdown in the TNBC and non-TNBC cell lines on proliferation, chemo sensitivity invasion competency and gene expression of target genes via quantitative real-time PCR were analyzed. Results: sFRP-1 (secreted frizzled related protein 1) and TCF7L2 (transcription factor-7 like 2) were identified as significantly over expressed genes in TNBC vs. non-TNBC and validated in an independent dataset. While sFRP-1 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. While mRNA knockdown of sFRP-1 in MDA-MB 468 was associated with an increased resistance to paclitaxel, doxorubicin and cisplatin, target gene expression analysis suggest sFRP-1 as a biphasic modulator in breast tissue. TCF7L2 knockdown analysis in the TN cell line MDA MB 231 as well as the non-TN lines MCF7 and SKBR-3 shows an increased cell invasiveness of up to 200 %. Conclusion: We suggest sFRP-1 as predictive biomarker and potential mediator of sensitivity to taxane-, anthracycline and platinum-containing chemotherapy in TNBC in vitro referring to its biphasic WNT modulation. Furthermore TCF7L2 is suggested as a prognostic biomarker in vitro breast cancer cell lines including TN and non-TN cell lines. Our results provide proof of principle that high-throughput gene expression analysis may be exploited as a means to derive at a biological / translational hypothesis that may be supported by basic science. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3024. doi:1538-7445.AM2012-3024