GSE28987
SRC-1 targets ADAM22: an ER-independent mechanism of tumour progression in endocrine resistance
We profile the binding of Steroid Receptor Co-activator (SRC1) in LY2 cells, a tamoxifen-resistant cell line, in the presence and absence of tamoxifen using ChIP-sequencing technology. The development of breast cancer resistance to endocrine therapy results from an increase in cellular plasticity leading to the development of a steroid-independent tumour.  The p160 steroid coactivataor protein SRC-1, through interactions with developmental proteins and other non-steroidal transcription factors, drives this tumour adaptability.  Here, using discovery studies, we identify ADAM22, a non-protease member of the ADAMs family, as a direct, ER-independent target of SRC-1. Molecular, cellular and in vivo studies confirmed SRC-1 as a regulator of ADAM22. At a functional level, a role for ADAM22 in cellular migration and differentiation was observed. In vivo data from a mouse xenograft model indicated that ADAM22 expression was higher in 4-OHT-treated endocrine-resistant tumours than in tumours derived from isogenic, sensitive cells.  Furthermore, in breast cancer patients, ADAM22 expression is an independent predictor of poor disease free survival.  SRC-1 can function as a molecular switch which converts a steroid-responsive tumour to a steroid-resistant tumour.  The ER-independent SRC-1 target ADAM22 is a potential drug target and a companion predictive biomarker in the treatment of endocrine-resistant breast cancer. Overall design: Examination of SRC-1 binding in LY2 cells in the presence or absence of tamoxifen treatment. 2 replicates each.