Artemin is estrogen regulated and mediates antiestrogen resistance in mammary carcinoma

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. Metaanalysis 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 estrogenindependent 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 smallinterfering 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.

Artemin, a Member of the Glial Cell Line-derived Neurotrophic Factor Family of Ligands, Is HER2-regulated and Mediates Acquired Trastuzumab Resistance by Promoting Cancer Stem Cell-like Behavior in Mammary Carcinoma Cells

“…Similarly, we have demonstrated previously that increased expression of ARTN is observed in tamoxifen-resistant ER ϩ mammary carcinoma cells and depletion of ARTN by siRNA partially restored tamoxifen sensitivity (16). Furthermore, increased ARTN expression has also been reported to be functionally associated with acquired resistance of ER Ϫ mammary carcinoma cells to paclitaxel and ionizing radiation and associated with ARTN promotion of the CSC phenotype (15).…”

“…tification of multiple and different factors and signaling pathways involved in acquired HER-2 resistance (2), it is likely and plausible that they are functionally interrelated and/or synergistic. Given the regulation of ARTN by estrogen (16) EGF, HRG, and IGF-1, ARTN regulation of VEGF (12) and ER activity (16), and as yet to be defined potential interactions with other molecules involved in trastuzumab resistance, it is possible that ARTN may be one common upstream mediator of resistance to HER-2 inhibition. That ARTN expression is increased in other examples of resistant cancer cell phenotypes (e.g.…”

“…ϩ mammary carcinoma cells (16). Furthermore, BCL-2 has been demonstrated to possess a functional role in the CSC-like population in mammary carcinoma (15,21) and including ARTN promotion of CSC-like behavior.…”

“…In addition, ARTN is an estrogen-inducible gene and mediates acquired antiestrogen (tamoxifen) resistance in mammary carcinoma. Depletion of ARTN partially restores tamoxifen sensitivity in ER ϩ tamoxifen-resistant cells (16). Depletion of ARTN also reverses acquired chemo-and/or radio-resistance via depletion of CSC population in ER-mammary carcinoma (15).…”

“…HER2-overexpressing cell lines possess a higher level of BCL-2 expression (19), and increased BCL-2 expression has been reported to contribute to the development of trastuzumab resistance (20). Previously, ARTN has also been demonstrated to regulate BCL-2 in mammary carcinoma (15,16) and enhance the CSC population in a BCL-2-dependent manner. Independently, CSCs have also been reported to utilize BCL-2 for survival (21).…”