Vitamin D counters bone invasion by mammary cancer through inhibition of inflammation and epithelial-to-mesenchymal transition

Vitamin D deficiency has been linked to poorer outcomes in various cancers, including breast cancer. Studies have shown that administering vitamin D or its analogs can help decrease tumor progression and metastasis in animal mammary cancer models. In a recent study, researchers investigated how vitamin D deficiency in mice contributes to bone invasion and metastasis of mammary cancer cells.

Using tibially-injected MMTV-PyMT mammary tumor cells, the researchers found that vitamin D deficiency in non-immunodeficient FVB mice accelerated bone invasion. Mechanistically, vitamin D deficiency increased pro-inflammatory cytokines and nestin expression in the internal bone surface and marrow. Additionally, vitamin D deficiency enhanced epithelial-to-mesenchymal transition (EMT) through the Zeb1 transcription factor.

In vitro experiments revealed that treatment of MMTV-PyMT tumor cells with CXCL12 stimulated Zeb1 expression. This effect was efficiently counteracted by administering 1,25(OH)2D, a form of vitamin D. Moreover, when MMTV-PyMT tumor cells were treated with 1,25(OH)2D, there was a significant reduction in several pro-inflammatory cytokines, such as GM-CSF, ICAM-1, IL-1ra, IP-10, JE, MCP-5, MIP-1, MIP-1β, MIP-2, RANTES, and CXCL12.

The researchers also found that vitamin D repleteness was associated with very high expression of Socs1, an inhibitor of the JAK/STAT pathway. This inhibitor prevents excessive inflammatory responses and has a tumor-suppressive role. These findings provide strong evidence linking vitamin D deficiency to accelerated inflammation-driven bone invasion, nestin expression, and EMT.

The study suggests that ensuring vitamin D repleteness in breast cancer patients could potentially enhance the efficacy of co-administered therapies in preventing invasion of skeletal sites.