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Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

Oncogene volume 29, pages 3228–3240 (2010)Cite this article

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A Corrigendum to this article was published on 19 January 2012

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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Article 23 September 2019

Nadia Harbeck, Frédérique Penault-Llorca, … Fatima Cardoso

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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Authors and Affiliations

  1. Liggins Institute, University of Auckland, Auckland, New Zealand

    J Kang, V Pandey, J K Perry, D X Liu & P E Lobie

  2. Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, PR China

    P X Qian & T Zhu

  3. Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    L D Miller

  4. Genome Institute of Singapore, Singapore

    E T Liu

  5. Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

    P E Lobie

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  1. J Kang
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Correspondence to P E Lobie.

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Competing interests

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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