RANK and EGFR in invasive breast carcinoma.

Breast cancer is the most common malignancy, affecting one in eight women in North America and Europe. The human epidermal growth factor receptor (EGFR) protein comprises a major determinant of normal development but also cancer. RANK receptor (Receptor Activator of Nuclear factor-κB) is a tumor necrosis superfamily member and a binding partner for RANKL, which was recently implicated in breast cancer initiation, progression and metastasis. Here we provide preliminary evidence of a possible interplay between RANK and EGFR signaling in breast cancer. TCGA (cancergenome.nih.gov) publicly available data for EGFR and TNFRSF11A (RANK) genes from breast cancer patients and breast cancer cell lines were retrieved and analyzed. RANK mRNA showed a statistically significant positive correlation (p <0.001) with the mRNA and protein expression of EGFR, but not with ERBB2/3/4. Further analyses of survival data of a group of breast cancer patients (n = 248) from TCGA, revealed an EGFRhi/RANKhi subpopulation that showed a statistically significant (p = 0.001) reduced overall survival when compared to EGFRlow/RANKlow group of patients. Finally, EGFR and RANK combinatorial in vitro analyses revealed a significant upregulation of AKT and ERK signaling after EGF stimulation in cell lines and also an increase of breast cancer cell invasiveness.