Abstract
BackgroundResistance to trastuzumab is a clinical problem, partly due to overriding activation of MAPK/PI3K signalling. Sprouty-family proteins are negative regulators of MAPK/PI3K signalling, but their role in HER2-therapy resistance is unknown.Patients and MethodsAssociations between Sprouty gene expression and clinicopathological features were investigated in a breast cancer microarray meta-analysis. Changes in expression of Spry2 and feedback inhibition on trastuzumab resistance were studied in SKBr3 and BT474 breast carcinoma cell lines using cell viability assays. Spry2 protein expression was measured by quantitative immunofluorescence in a cohort of 122 patients treated with trastuzumab.ResultsLow gene expression of Spry2 was associated with increased pathological grade, high HER2 expression, and was a significant independent prognostic factor. Overexpression of Spry2 in SKBr3s resulted in enhanced inhibition of cell viability after trastuzumab treatment, and 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. Stratification of trastuzumab-treated patients using PTEN and Spry2 was superior to either marker in isolation.ConclusionIn breast cancers with deficient feedback inhibition, combinatorial therapy with negative regulators of growth factor signalling may be an effective therapeutic strategy.
Highlights
The HER2-targeting receptor tyrosine kinase (RTK) inhibitor trastuzumab (Herceptin) has clinical efficacy in both early and metastatic breast cancer, measurement of HER2 protein expression or gene amplification status is a relatively poor predictor of response with a low positive predictive value [1,2]
Overexpression of Spry2 in SKBr3s resulted in enhanced inhibition of cell viability after trastuzumab treatment, and 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
Summary
The HER2-targeting receptor tyrosine kinase (RTK) inhibitor trastuzumab (Herceptin) has clinical efficacy in both early and metastatic breast cancer, measurement of HER2 protein expression or gene amplification status is a relatively poor predictor of response with a low positive predictive value [1,2]. Suggested mechanisms of de novo and acquired resistance to trastuzumab include PIK3CA activating mutations, PTEN inactivation, IGF1R over-expression and expression of p95 HER2 isoforms [3,4,5]. We hypothesised that one of the best characterised and potent EGF-induced negative feedback regulators, the Sproutyfamily of proteins [6,7,8,9,10,11,12], may be activated as a feedback inhibition programme downstream of HER2 receptor, and contribute to sensitivity or resistance to trastuzumab. Resistance to trastuzumab is a clinical problem, partly due to overriding activation of MAPK/PI3K signalling. Sprouty-family proteins are negative regulators of MAPK/PI3K signalling, but their role in HER2-therapy resistance is unknown
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
