Developmental protein HOXC11 cooperates with SRC-1 in breast cancer: an adaptive response to endocrine therapy

The ability of a tumour to adapt and overcome targeted therapies has been recognised clinically for some time, but the molecular mechanisms driving this metamorphosis remain unclear. The steroid receptor coactivator protein, SRC-1, is a strong predictor of reduced disease-free survival in breast cancer patients. SRC-1 can also interact with nonsteroidal transcription factors, and defining these new transcriptional networks will uncover fresh strategies for managing endocrine resistance.

Here we employed a mass spectrometry-based screen to identify proteins that are specific to the endocrine-resistant phenotype. The developmental protein, HOXC11, was identified and functionally validated as an interaction partner of SRC-1. We provide evidence that HOXC11 and SRC-1 cooperate to regulate expression of the calcium binding protein S100β in resistant breast cancer cells. Moreover, both nuclear HOXC11 and S100β 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 S100β detected in patients also predicted reduced disease-free survival (n = 80; hazard ratio = 5.3; P = 0.004). This translational study identifies a biomolecular interaction network central to the adaptive response to endocrine therapy with clear clinical applications.