RANKL Signaling and ErbB Receptors in Breast Carcinogenesis

ErbB family members, ErbB1/EGFR/HER-1, ErbB2/HER-2, ErbB3/HER-3 and ErbB4/HER-4, have been implicated in breast cancer (BC) tumorigenicity. Recently, crucial roles for RANK/RANKL signaling in addition to key downstream factor NF-kappa B have been demonstrated in mammary tumorigenesis. Here, we present the hypothesis of a novel association between ErbB and RANK pathways in promoting BC. The proposed model alludes to the crosstalk that might occur between RANK and ErbB receptors. This interplay might regulate RANK signaling and consequently, modulate carcinogenesis, mainly in ErbB2 over-expressing BC cells. Thus, we highlight the significance of the RANK/RANKL axis as a putative therapeutic target in this malignancy, and furthermore, suggest that the combination of ErbB and RANK/RANKL inhibitors may have therapeutic benefit for certain BC patients.