Artemin (ARTN) is a growth factor belonging to the glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFL) comprised of 4 members including GDNF, neurturin and persephin. In addition to its described neurotrophic role [1–3], ARTN has also been implicated in promoting oncogenicity, tumor growth and invasiveness in diverse human malignancies, including mammary, endometrial, esophageal, lung and pancreatic carcinoma [4–10].
In mammary carcinoma (MC), increased expression of ARTN has been observed compared to normal tissue and expression of ARTN in MC predicted residual disease after chemotherapy, metastasis, relapse, and death . It has been reported that forced expression of ARTN promotes tumor growth by increased proliferation and survival [5, 7, 8]. Furthermore, ARTN promotes epithelial to mesenchymal transition and angiogenesis and enhances cancer stem cell like behaviour in ER-negative MC (ER-MC) carcinoma cells resulting in metastatic dissemination [5, 11–13]. Moreover increased ARTN expression predicts poor survival of patients with ER-positve MC (ER + MC) treated with tamoxifen and forced expression of ARTN produces anti-estrogen resistance . The downstream signaling pathways by which ARTN promotes cell survival, oncogenicity, drug resistance [6, 7, 14] and metastases  have been reported. However, the prognostic significance of upstream ligand binding components, potentially mediating ARTN oncogenicity in mammary carcinoma, remain to be determined.
GFL family members were initially thought to signal via high affinity preferential interaction with one or more of the GDNF receptor α family (GFRα) comprising GFRα1-4 [1–3]. The GFL- GFRα complex then binds to and activates the transmembrane RET receptor tyrosine kinase  which propagates cellular signaling. However, GFLs are promiscuous and interact with multiple GFRα family members, ARTN having been reported to bind and activate both GFRα1 and GFRα3 . Moreover, GFLs have been reported to bind to and/or activate distinct non-GFRα proteins  and to function by both RET dependent and independent mechanisms [4, 16, 17]. Recently ARTN, as well as GDNF, has been reported to activate signaling through c-Src by binding to Syndecan-3 (SDC3) . Increased GFRα1 expression has been previously reported in MC and its expression is associated with certain clinicopathologic features such as lymph node metastases . However, no correlation of expression with survival outcome of patients was determined. To date, the expression and prognostic significance of GFRα3 and SDC3, the two other receptor proteins binding ARTN in MC has not been reported.
In an attempt to determine which of the ARTN binding proteins identified to date may mediate the effects of ARTN in MC, we examined the mRNA and protein expression of GFRα1, GFRα3 and SDC3 in MC and examined the correlation of expression to clinicopathologic features and patient survival outcome, both by univariate and multivariate analyses. Moreover, we correlated the combined expression of ARTN and the various receptors with patient survival outcome to determine which combination of ligand and receptor may represent the functional complex mediating mammary neoplastic progression.