Despite great advances in the diagnosis, management and treatment of breast cancer (BC), its metastasis to distant organs still poses a significant clinical challenge. Secondary BC in the bone is a devastating progression of the original disease, remains incurable and has a poor prognostic outlook. In 2019, the 5-year survival rate of BC was 91% in Australia; for metastatic BC, the 5-year survival rate dropped to just 32%. Monocyte chemoattractant protein-1 (MCP-1) is a chemotactic protein that is implicated in bone resorption and BC progression. MCP-1 expression is increased in diseases of excess bone resorption, such as osteoporosis. Our aim was to identify a role of MCP-1 in BC bone metastasis, investigate the therapeutic effects of MCP-1 inhibition on metastatic burden within bone, and determine whether there is an increased risk of BC bone metastasis associated with pre-cancer osteoporosis. We hypothesised that increased MCP-1 expression is associated with BC bone metastatic disease.
Ovariectomised (OVX; n = 19) and sham-operated (SHAM; n = 18) female BALB/c mice were challenged with the 4T1.2 murine BC cell line. Mice were administered a plasmid DNA encoding 7ND, a mutant, dominant-negative form of MCP-1 that inhibits its action (OVX, n=9; SHAM, n = 9), or an empty vector as a control (OVX, n = 10; SHAM, n = 9). Mice were sacrificed 3-weeks post-4T1.2 challenge. Tibial microCT analysis showed significant increases in trabecular bone volume and trabecular number in 7ND-treated OVX mice (p < 0.05). Flow cytometry analysis of bone marrow showed changes in cell population abundance. Nanostring analysis showed significant downregulation of genes associated with cancer and osteoclastogenesis pathways in the 7ND-treated OVX mice (p < 0.05). Our findings suggest a critical role of MCP-1 in BC-related bone loss, presenting MCP-1 as a potential treatment target and introducing 7ND as a potential therapeutic.