Expression Profile of Receptor Activator of Nuclear-κB (RANK), RANK Ligand (RANKL) and Osteoprotegerin (OPG) in Breast Cancer

Background: Breast cancer, the most common cancer affecting women in the USA and UK, is known to have a high frequency of osteolytic bone metastasis. Receptor activator of nuclear-kappa B (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG) are a group of important regulators for osteoclast differentiation and activation. These molecules have been implicated in bone metastasis. Since the discovery of the triad of RANK, RANKL and OPG in healthy bone turnover, a better understanding of these factors in bone metastasis has been sought. Materials and Methods: Using our clinical breast cancer cohort, the transcript levels of RANK, RANKL and OPG were examined using real-time quantitative-polymerase chain reaction (qPCR). Expression of these molecules in the immortalised breast cancer cell lines MCF-7 and MDA-MB-231 was also analyzed using qPCR following treatment with beta-oestradiol in a concentration-dependent manner. Results: RANK, RANKL and OPG were all shown to be expressed in the breast cancer cell lines examined. Transcript levels were shown to be reduced in tumour samples when compared with normal tissue. Reduced RANK expression was associated with a worse clinical outcome and levels were significantly reduced in patients with general metastasis, bone metastasis and those who had died of the disease. Patients with reduced RANKL expression were more likely to develop local recurrence, bone metastasis or die from the disease. Using Kaplan-Meier survival analysis, lower expression levels of OPG were found to be associated with significantly better overall patient survival in our cohort. Conclusion: The corresponding prognostic and therapeutic potential is yet to be further investigated. Our data suggest that RANK, RANKL and OPG may potentially be used as novel prognostic markers for bone metastasis and provide new therapeutic targets in the treatment of breast cancer.