Abstract
Abstract BackgroundThe nuclear receptor co-activator SRC-1 has recently been implicated as an important mediator of breast cancer metastasis in vitro. These findings are in keeping with previous reports from our group reporting significantly reduced disease free survival in patients who express SRC-1 when compared to those who do not. We identified the developmental protein HOXc11 as interacting with SRC-1 in tamoxifen resistant breast cancer cells. Dysregulation of homeobox genes has been reported in a wide variety of both solid organ and haematological malignancies. The putative target gene of HOXc11, S100B is a secreted protein, known to be of prognostic significance in malignant melanoma. The aim of this work was to examine the relationship between HOXc11, SRC-1 and S100B and their relevance to disease progression in breast cancer.Materials and MethodsAll chromatin immunoprecipitation (ChIP) and proliferation assays were performed in tamoxifen resistant breast cancer cells derived from MCF7s. Immunohistochemistry was performed for S100B, HOXc11 and SRC-1 on a tissue microarray of 560 patients with invasive breast cancer with a median follow up of 6.5 years. S100B was assessed using an ELISA based technique (Diasorin, USA) on serum samples of a prospective cohort of patients with breast cancer prior to any treatment.ResultsChIP assays confirmed recruitment of both HOXc11 and SRC-1 to the promoter region of S100B after treatment with tamoxifen at both 45 minutes and 2 hours when compared to control. Treatment of tamoxifen resistant cells with HOXc11 siRNA resensitised the cells to the anti-proliferative effects of tamoxifen. Immunohistochemistry revealed S100B to be a strong predictor of reduced disease free survival in patients receiving adjuvant endocrine treatment (Hazard ratio 5.82; p<0.0001). Tumour expression of S100B was associated with expression of both HOXc11 and SRC-1 providing translational evidence for a relationship between these proteins. Elevated serum levels (>0.15ug/l) of S100B were found in 10.5% of patients with breast cancer prior to treatment. Elevated S100B correlated with HER2 positivity (Fisher's exact: p=0.005) but not with any of the other standard clinico-pathological factors examined. From a cohort of 80 patients with known medium to long term follow up, elevated serum S100B showed a strong positive correlation with disease recurrence (p=0.017, odds ratio 9.38).DiscussionOur investigations into the prognostic significance of S100B in breast cancer have shown considerable promise. Given it's accessibility as a serum protein, quantifiable by ELISA, it offers potential as a marker for disease recurrence in patients with breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4052.
Published Version
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