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      Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma.


      Breast Neoplasms, drug therapy, genetics, metabolism, pathology, Cell Line, Tumor, Drug Resistance, Neoplasm, Estradiol, pharmacology, Estrogen Receptor Modulators, Female, Gene Expression Regulation, Neoplastic, drug effects, Humans, Neoplasm Invasiveness, Nerve Tissue Proteins, antagonists & inhibitors, biosynthesis, Proto-Oncogene Proteins c-bcl-2, RNA, Small Interfering, Receptors, Estrogen, Tamoxifen, Transcription, Genetic

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          We have previously identified an oncogenic role of artemin (ARTN), a member of glial cell derived neurotrophic factor family of ligands, in mammary carcinoma. We herein report that ARTN is an estrogen-inducible gene. Meta-analysis of gene expression data sets showed that ARTN expression is positively correlated to estrogen receptor (ER) status in human mammary carcinoma. Furthermore, in patients with ER-positive mammary carcinoma treated with tamoxifen, high ARTN expression is significantly correlated with decreased survival. Forced expression of ARTN in ER-positive human mammary carcinoma cells increased ER transcriptional activity, promoted estrogen-independent growth and produced resistance to tamoxifen and fulvestrant in vitro and to tamoxifen in xenograft models. ARTN-stimulated resistance to tamoxifen and fulvestrant is mediated by increased BCL-2 expression. Conversely, depletion of endogenous ARTN by small-interfering RNA or functional antagonism of ARTN by antibody enhanced the efficacy of antiestrogens. Tamoxifen decreased ARTN expression in tamoxifen-sensitive mammary carcinoma cells whereas ARTN expression was increased in tamoxifen-resistant cells and not affected by tamoxifen treatment. Antibody inhibition of ARTN in tamoxifen-resistant cells improved tamoxifen sensitivity. Functional antagonism of ARTN therefore warrants consideration as an adjuvant therapy to enhance antiestrogen efficacy in ER-positive mammary carcinoma.

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