Abstract
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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Abbreviations
- ARTN:
-
artemin
- BrdU:
-
bromodeoxyuridine
- CS-FBS:
-
charcoal stripped-fetal bovine serum
- DMFS:
-
distant metastasis-free survival
- ER:
-
estrogen receptor
- ERE:
-
estrogen response element
- GDNF:
-
glial cell derived neurotrophic factor
- GFL:
-
GDNF family of ligand
- GFRα:
-
GDNF family receptor-α
- OAS:
-
overall survival
- PR:
-
progesterone receptor
- qPCR:
-
quantitative PCR
- siRNA:
-
small-interfering RNA
- TUNEL:
-
terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling
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Acknowledgements
We thank Carol Chelimo (MPH) for the meta-analysis of breast cancer microarray data. This work was funded by the Breast Cancer Research Trust (NZ); the Foundation for Research, Science and Technology of New Zealand; the Hundred-Talent Scheme of Chinese Academy of Sciences, National Natural Science Foundation of China (30571030) and National Basic Research Program of China (2007CB914503).
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JK, VP, JKP, DXL and PEL have equity interests in Saratan Therapeutics Ltd. DXL and PEL are inventors on PCT application PCT/NZ2008/000152 and US provisional applications 61/234902. PEL is an inventor on US provisional application 61/252513. TZ and PEL are consultants for Saratan Therapeutics Ltd.
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Kang, J., Qian, P., Pandey, V. et al. Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma. Oncogene 29, 3228–3240 (2010). https://doi.org/10.1038/onc.2010.71
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DOI: https://doi.org/10.1038/onc.2010.71
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