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.
Authors and Affiliations
Royal College of Surgeons in Ireland, Dublin, Ireland
McIlroy, M., McCartan, D., Early, S. et al. Developmental protein HOXC11 cooperates with SRC-1 in breast cancer: an adaptive response to endocrine therapy.
Breast Cancer Res12
(Suppl 1), P21 (2010). https://doi.org/10.1186/bcr2518