PO-518 Biomarker signature defines a potential therapeutic subclass of triple negative breast cancer

Abstract

IntroductionTriple Negative Breast Cancer (TNBC) is associated with a worse prognosis among breast cancer subtypes due to the lack of targeted therapy. The protein phosphatase 2A (PP2A) is a heterogeneous tumour suppressor complex that is tightly regulated in terms of activity and target specificity. Oncogenic inactivation of PP2A is known to be mediated by various mechanisms. The overexpression of inhibitory regulators and increased phosphorylation of PP2A targets have been associated with the TNBC subtype and a worse prognosis. PP2A is predicted to be deregulated in 60% of TNBC and presents a potential target for therapy. Here, we use novel biomarkers, AURKA and KIF2C to identify a TNBC subclass with actionable PP2A deregulation.Material and methodsA transcript and protein biomarker signature is established in 12 breast cancer cell lines. Sensitivity to PP2A activator, FTY720 was measured by MTT assays and a PP2A activity assay was performed following immunoprecipitation of the phosphatase. Expression of AURKA and KIF2C transcript is measured from 160 histopathologically annotated TNBC samples using a branched DNA assay. Protein expression of biomarkers was also assessed by immunohistochemistry using the H-score from two independent scorers to identify tumours potentially sensitive PP2A activation.Results and discussions3 out of 6 TNBC cell lines are sensitive to PP2A activation by FTY720. Sensitive cell lines show elevated expression of biomarkers which are attenuated following treatment. 65% of TNBC patients overexpress AURKA while 40% overexpress KIF2C when compared to normal breast epithelium expression. Tumours overexpressing both markers are associated with a more aggressive subclass of tumours and are potentially eligible to PP2A activation therapy. The cell line model is used to define a novel subclass of tumours.The biomarker signature predicts a novel therapeutic class of TNBC with suppressed PP2A activity that results in activated cellular proliferation.ConclusionPP2A activity biomarkers were found to be commonly overexpressed within the TNBC subtype. Our cellular models elicit further validation of this biomarker signature xenografts. Re-activating the PP2A tumour suppression mechanism is expected to target specific malignant mechanisms in TNBC with minimal effect to normal tissues.