Recurrence in HER2 over-expressing breast cancer-a predictive role for PEA3 and SRC-1

Abstract

Abstract Introduction: Regulation of HER2 through the transcription factor PEA3 is associated with tumour progression and resistance to endocrine treatment in human breast cancer. The mechanism of this resistance remains unclear. Activation of estrogen receptor co-activator proteins via the MAP-kinase pathway is thought to be central to tamoxifen insensitivity. We hypothesised that activation of HER2 by PEA3 may result in activation of co-activator proteins such as AIB1 (amplified-in-breast-cancer) and SRC-1 (steroid co-activator), resulting in endocrine resistance. Methods: In primary breast cultures, growth factor induction of PEA3-HER2 promoter interaction was assessed using mobility-shift analysis and protein expression by western-blot. Expression of PEA3 and the co-activators was localised and co-localised in a cohort of patients using immunohistochemistry and immunofluorescence. Expression was correlated with clinicopathological parameters. Results: Binding of PEA3 to the HER2 promoter was increased by growth factors, bFGF and EGF. Growth factors were found to up-regulate the protein expression of PEA3 and the co-activators in primary breast cell cultures (n = 12). PEA3 expression was localised to the breast epithelial cells and was found to be co-expressed with AIB1 and SRC-1. HER2 expression was found to be associated with PEA3, AIB1 and SRC-1 (n = 72, p=0.0041, 0.0038 and 0.001 respectively). Moreover, by the odds ratio, patients that were both HER2 positive and SRC-1 positive had a 97% probability of recurrence, compared with a 5% probability in HER2 patients that were SRC-1 negative. Conclusions: The mechanisms of recurrence in HER2 positive breast cancer may be explained by the activation of the co-regulatory protein SRC-1.