Key Players and Potential Therapies in the Development of Breast Cancer Metastasis to the Spine

Abstract

Background: Breast cancer metastasis to the spine causes severe morbidity due to pathological fractures, spinal cord compression, pain, loss of mobility and paralysis. An improved understanding of the biology behind metastatic breast cancer growth and invasion to the bony vertebral column is essential in order to control local tumour growth and progression of metastasis.

Aim: To identify and characterise the presence of six key markers involved in spinal metastasis progression, RANKL, OPG, MMP-9, PTHrP, VEGF and IL-6. To determine the effectiveness of inhibitory agents, bisphosphonate Zoledronic Acid and RTK inhibitor Sorafenib on cancer cell growth and survival, as well as the expression of tumour markers in vitro.

Materials and Methods and Results: The presence of RANKL, OPG, MMP-9, PTHrP, VEGF and IL-6 was confirmed in the cytoplasm of secondary breast cancer cell lines MDA-MB-231, MDA-MB-453 and MCF-7 in vitro. This was further supported by histological analysis of tumour-containing spinal sections from an established mouse model of spinal cancer. Zoledronic Acid and Sorafenib reduced proliferation rates in all cell lines and Sorafenib caused significant apoptosis of MDA-MB-231 and MDA-MB-453 cells.

Conclusion: This study highlights a potential role for the markers VEGF, RANKL and IL-6 in promoting breast cancer growth, bone degradation and angiogenesis during spinal metastases. Both Zoledronic Acid and Sorafenib displayed anti-tumour effects on cancer proliferation and to a lesser extent apoptosis. These findings highlight the importance of tumour and bone-derived factors and their therapeutic application in breast cancer spinal metastasis.