We also present data suggesting that the combination of anti-ERBB-2 agents and RANKL inhibitors have a potential direct anti-tumor effect and should be further tested in certain BC patients.Īccording to global statistics, breast cancer (BC) is the most common cancer in the female population. The results indicate a novel physical and molecular association between ERBB-2 and RANK pathways that affects ERBB-2 (+) BC growth. Denosumab suppressed NF-κB signaling and diminished proliferation rate in MDA-MB-453 cells. The combination treatment of SKBR3 with D, T, and P had an advantage in functional traits compared to single targeting. In SKBR3, RANKL and ERBB-2 blockage resulted in reduced cell proliferation, increased apoptosis, and lower metastatic potential compared to mock cells (m) and reversed values in RANKL presence. Combination targeting of SKBR3 further decreased NF-κB pathway activation compared to single targeting. RANK/ERBB-2 dimers were decreased in the presence of the inhibitors D, T, and P, while they were increased after RANKL (R) treatment in SKBR3 (m, 5.4 D, 1.2 T, 1.9 DT, 0.6 TP, 1 DTP, 0.4 R, 11.8) and BT-474 (m, 8.2 D, 3.1 T, 4.3 DT, 0.7 TP, 3.4 DTP, 3.2 R, 11.6). RANK/ERBB-2 dimer number seems to be associated with ERBB-2 expression (SKBR3, 5.4 BT-474, 8.2 MCF7, 0.7 MDA-MB-453, 0.3). RANK receptor dimerizes with ERBB family members. RANK immunostaining was also detected in human BC tissue samples. ResultsĬell lines express RANK and RANKL. For cell migration evaluation, scratch assay was performed. Cell growth and viability was evaluated using XTT, flow cytometry, and clonogenic assay. NF-κB pathway activation was studied using Western blot. The interaction between RANK and ERBB family members was detected using proximity ligation assay (PLA), which enables the visualization of interacting proteins. The evaluation of RANK expression in a cohort of BC patients was performed using immunohistochemistry. We examined RANK and RANKL expression using RT-PCR, Western blot, and immunofluorescence. We used SKBR3, MCF7, MDA-MB-453, and BT-474 human BC cell lines. The purpose of this study was to elucidate the underlying molecular mechanism of this interaction and the beneficial impact of dual targeting of RANK and ERBB-2 pathways. The receptor activator of nuclear factor-κB (RANK) pathway is implicated in ERBB-2 (+) BC. ERBB-2 is overexpressed in about 20% of breast cancers (BCs), indicating poor prognosis.
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