Prognostic significance of the expression of GFRα1, GFRα3 and Syndecan-3, proteins binding ARTEMIN, in mammary carcinoma

Background: Artemin (ARTN) has been implicated in promoting oncogenicity, tumor growth and invasiveness in diverse human malignancies. However, the clinical and prognostic significance of upstream ligand binding components, potentially mediating ARTN oncogenicity, largely remain to be determined. Methods: We determined the mRNA and protein expression of three proteins demonstrated to bind ARTN, namely GFR alpha 1, GFR alpha 3 and Syndecan-3 (SDC3), in benign breast disease and mammary carcinoma by in situ hybridization and immunohistochemistry, respectively. Their prognostic significance combined with ARTN expression was also investigated in mammary carcinoma. Results: The expression of GFR alpha 1 and GFR alpha 3, but not SDC3, was significantly increased in mammary carcinoma and positively associated with tumor lymph node metastases, higher clinical stage and HER-2 positivity. Moreover, both GFR alpha 1 and GFR alpha 3 expression were significantly associated with survival outcome of patients with mammary carcinoma by univariate and multivariate analyses, whereas expression of SDC3 was not. Co-expression of ARTN with either GFR alpha 1 or GFR alpha 3, but not SDC3, produced synergistic increases in the odds ratio for both relapse-free and overall survival in patients with mammary carcinoma. Furthermore, significant association of GFR alpha 1 and GFR alpha 3 expression with survival outcome observed herein were restricted to ER negative or HER-2 negative mammary carcinoma. Conclusions: The expression of GFR alpha 1 and/or GFR alpha 3, especially when combined with ARTN expression, may be useful predictors of disease progression and outcome in specific subtypes of mammary carcinoma.