LB57
The developmental protein HOXC11 cooperates with SRC-1 in breast cancer: an adaptive response to endocrine therapy
Marie McIlroy1, Damian McCartan1, Sarah Early1, Stephen Pennington2, Peadar O'Gaora2, Arnold Hill1, Leonie Young1
1Royal College of Surgeons in Ireland, Dublin, Ireland; 2 Unviversity College Dublin, Ireland
The ability of a breast tumour to adapt and overcome targeted therapies has been recognised clinically for some time, but the molecular mechanisms driving this metamorphosis remain unresolved. The steroid receptor coactivator protein, SRC-1 is a strong predictor of reduced disease-free survival in breast cancer patients and recent in-vivo studies have confirmed a role for SRC-1 in the promotion of metastasis. SRC-1 can also interact with non-steroidal transcription factors and defining these new transcriptional networks will uncover fresh strategies for managing endocrine resistance.
Here we employed a MALDI-TOF mass spectrometry-based screen to isolate proteins which are specific to the endocrine resistant phenotype. The developmental protein, HOXC11, was identified and functionally validated as an interacting partner of SRC-1. We provide evidence that HOXC11 and SRC-1 cooperate to regulate expression of the calcium binding protein S100beta in endocrine resistant breast cancer cells. Moreover, both HOXC11 and S100beta were found to be strong predictors of poor disease-free survival in breast cancer patients (n=560; hazard ratios: 5.79 and 5.82, respectively; p<0.0001). Elevated serum levels of S100beta were found in a subset of breast cancer patients and associate significantly with disease recurrence (n=80). This translational study identifies a biomolecular interaction network central to the adaptive response to endocrine therapy with clear clinical applications.
