Abstract
Abstract Breast cancer affects one woman in ten in the western world and despite the phenomenal advances in recent years, the mortality rate still remains at around 35%. Resistance to current endocrine therapies, including tamoxifen and aromatase inhibitors, is common with recurrence of disease in 30-40% of patients. The estrogen receptor (ER) coactivator protein SRC-1 plays an important role in this resistance. We examined SRC-1 protein expression in a large cohort of breast cancer patients (n=560) and found expression to be a strong predictor of disease recurrence in patients treated with adjuvant tamoxifen (hazard ratio: 5.032, p<0.0001). Identification of SRC-1 interacting proteins will provide key insights into the role of SRC-1 in the development of tumour recurrence. We employed a mass spectrometry-based screen to identify proteins which could differentially interact with SRC-1 in endocrine resistant compared with endocrine sensitive breast cancer cells. Selected SRC-1 interacting proteins relevant to endocrine resistance include the high mobility proteins HMGB1 and HMGB2, which have previously been reported to enhance binding of the estrogen receptor to its response elements in target gene promoters. Immunoprecipitation assays confirmed increased interactions between HMGB2 and SRC-1 following treatment of the endocrine resistant cell line LY2 with tamoxifen and estrogen. Steroid treatment also increased trafficking of the coactivator and the SRC-1 interacting protein to the nucleus of tumour epithelial cells. Treatment enhanced recruitment of SRC-1 to the promoter of the oncogene c-Myc and enhanced target gene expression. HMGB2 expression in the breast cancer patient TMA correlated with SRC-1 and poor disease-free survival. These findings would indicate an important role for HMGB2 in the development of endocrine resistance in breast cancer patients. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5138.
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