Abstract P5-05-06: The Role of Sprouty 2 in HER2 Signaling in Breast Cancer; Decreased Expression Is Associated with Poor Outcome Including in Trastuzumab-Treated Patients

Purpose: Resistance to trastuzumab is a frequent clinical problem, in part due to the overriding activation state of the MAPK/PI3K signaling pathways. Sprouty-family proteins are negative regulators of MAPK/PI3K signaling, but their role in HER2 signaling and resistance to therapy is unknown. Experimental design: The association of Sprouty 2 gene expression with grade, HER2-status, and survival was investigated in a meta-analysis of 1107 breast tumors from six published microarray studies. Sprouty regulation in response to HER2/HER3 signaling was studied using qRT-PCR. Changes in expression of Spry2 and feedback inhibition on trastuzumab-resistance were studied using full-length/dominant-negative transfection or chemical inhibition in SKBr3 and BT474 cell lines in cell viability assays. Finally, expression of Spry2 was measured in a cohort of 122 patients treated with trastuzumab by quantitative fluorescence microscopy (AQUA). Results: Low Spry2 gene expression was associated with high HER2 protein expression. Spry2 was regulated through HER2/HER3 signaling as a delayed early gene, an effect reversed by treatment with the dimerization inhibitor pertuzumab. Overexpression of Spry2 in the SKBr3 trastuzumab-resistant cell line resulted in synergistic inhibition of cell viability with trastuzumab. Restitution of feedback inhibition with the PI3K-inhibitor LY294002 had a similar effect. Low Spry2 expression was associated with increased risk of death (HR = 2.28, 95% CI 1.22 - 4.26; p=0.008) in trastuzumab-treated patients, including in multivariate analysis (Cox regression analysis, p=0.002). Conclusions: These results suggest that combinations of negative regulators of growth factor signaling may be an effective therapeutic strategy in breast cancers with deficient feedback inhibition. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-05-06.