Estrogen signaling is critical in the progression of a large fraction of breast cancers as well as in the maintenance of bone mineral density. Generally speaking, Tamoxifen, a selective estrogen receptor modulator (SERM), blocks estrogen signaling in the breast by acting as an antagonist at the same time as promoting estrogen signaling in the bone by acting as an agonist. This tissue specific action characteristic of SERMs is thought to be maintained by the balance of levels and/or activities of estrogen receptor (ER) coregulators. Because of this critical role, single nucleotide polymorphisms (SNPs) in ER coregulators could have a dramatic effect on tamoxifen action.Previous studies have implicated steroid receptor coactivator-1 (SRC-1) as a critical coregulator for the mixed antagonist-agonist specificity of tamoxifen. By using an ERE-Tk-Luciferase transient transfection assay, we have shown that a SNP causing the amino acid change P1272S in SRC-1 dramatically reduces its ability to coactivate ERα.To assess the impact of this SNP on tamoxifen action in breast cancer we decided to genotype the SRC-1 P1272S SNP in a breast tumor DNA bank. This bank was generated from archived tumors from individuals either exclusively receiving adjuvant tamoxifen or not receiving any adjuvant therapy following surgical resection. Currently, the bank is composed of 1000 samples divided equally among the two groups. Genotyping for the SRC-1 P1272S SNP is currently underway.Since SRC-1 has also been shown to be important in proper maintenance of bone mineral density (BMD) and in the agonist action of tamoxifen in certain tissues, we also assessed the impact of the P1272S SNP in bone following tamoxifen therapy. We genotyped breast cancer patients exclusively receiving tamoxifen therapy (i.e. no chemotherapy, no radiation) who had lumbar (n=113) and/or hip (n=108) BMD scans before and after 12 months of tamoxifen therapy. We observed a significant association between the SNP and bone loss; women harboring the P1272S SNP lost 6.4% of their lumbar BMD, while women with the WT version lost only 1.3% of their lumbar BMD.These findings illustrate the critical role of SRC-1 in tamoxifen action in bone, and potentially other hormone responsive tissues. Studies are ongoing to decipher the mechanism for decreased coactivation activity of the SNP, and also to extend the clinical association studies.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 66.
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