Tamoxifen-induced ER-alpha-SRC-3 interaction in HER2 positive human breast cancer; a possible mechanism for ER isoform specific recurrence.
Differential signalling between the two oestrogen receptor (ER) isoforms in the presence of tamoxifen has been described. We hypothesise that differential recruitment of the steroid receptor co-activator, SRC-3 to ER-alpha and ER-beta may in part explain associations between ER isoforms and response to endocrine treatment. SRC-3 was localised within epithelial cells of breast tumour tissue and was co-localised with ER-alpha and ER-beta, (n=112). Expression of SRC-3 was found to be positively associated with ER-alpha (P=0.0021) and inversely with ER-beta (P<0.0001). Uniquely, this study utilises primary cell cultures derived from patient tumours, thus providing samples not readily available in most molecular model systems. These samples have enabled us to investigate the influence of growth factor pathways on steroid receptor-co-activator interactions. In HER2 (human epidermal growth factor receptor 2) positive primary tumour cell cultures 17beta-estradiol induced a decrease in SRC-3, whereas upregulated SRC-3 expression. Furthermore, treatment with tamoxifen-induced SRC-3 recruitment to the ER-oestrogen response element and enhanced interaction between SRC-3 and ER-alpha, but not ER-beta. Knockdown of SRC-3 results in a concomitant loss of expression of the oestrogen target gene pS2. Furthermore, silencing of SRC-3 resensitizes endocrine resistant, HER2 positive cells to the anti-proliferative effects of tamoxifen. The ability of ER-alpha, but not ER-beta to recruit SRC-3 in the presence of tamoxifen may in part explain the differential ER isoform associations with recurrence in human breast cancer.
Pubmed ID: 17158759 RIS Download
Antineoplastic Agents, Hormonal | Blotting, Western | Breast Neoplasms | Cell Proliferation | Drug Resistance, Neoplasm | Electrophoretic Mobility Shift Assay | Estrogen Receptor alpha | Estrogen Receptor beta | Female | Fluorescent Antibody Technique | Histone Acetyltransferases | Humans | Immunoprecipitation | Middle Aged | Neoplasm Recurrence, Local | Neoplasms, Hormone-Dependent | Nuclear Receptor Coactivator 3 | Presenilin-2 | Promoter Regions, Genetic | Receptor, ErbB-2 | Response Elements | Tamoxifen | Trans-Activators | Tumor Cells, Cultured