Researchers have identified a molecular pathway that helps explain why certain subtypes of triple negative breast cancer are more likely to spread to bone, shedding new light on the mechanisms driving organ-specific metastasis and highlighting potential therapeutic targets.
Breast cancer metastasis often follows predictable patterns, with different subtypes showing preferences for specific organs. In triple negative breast cancer, which lacks oestrogen, progesterone and HER2 receptors, outcomes are particularly poor once distant spread occurs. Understanding what drives this organ tropism is critical for developing strategies to prevent or treat metastatic disease.
Distinct Metastatic Pattern In TNBC Subtypes
Using retrospective analyses of public metastatic datasets, investigators found that the luminal androgen receptor subtype of triple negative breast cancer showed a markedly higher propensity for bone metastasis compared with other TNBC subtypes. This observation suggested a possible role for androgen receptor signalling in directing tumour cells to the bone microenvironment.
To explore this further, researchers used mouse models of triple negative breast cancer alongside single-cell sequencing approaches. These experiments demonstrated that activation of the androgen receptor significantly promoted bone metastasis in luminal androgen receptor tumours, confirming a functional role for this pathway in metastatic spread rather than a simple association.
Role of Androgen Receptor and c-Myc
Single-cell sequencing analysis revealed that c-Myc, a well-known oncogenic transcription factor, played a central role in androgen receptor mediated bone metastasis. Immunoprecipitation experiments confirmed a direct interaction between androgen receptor and c-Myc, suggesting that these two proteins act together to regulate downstream effects within the bone microenvironment.
Further investigation focused on how this interaction altered the behaviour of immune and bone-resident cells. Analyses of the bone microenvironment showed that androgen receptor and c-Myc signalling promoted differentiation along the macrophage to osteoclast axis. Osteoclasts are responsible for bone resorption, a process commonly exploited by metastatic cancer cells to establish and expand bone lesions.
Implications For Bone Metastasis Treatment
The study found that androgen receptor c-Myc interaction enhanced macrophage activation and osteoclast differentiation through increased expression of matrix metalloproteinase 13, leading to greater bone degradation. This bone resorption creates a favourable niche for tumour growth, helping explain the strong bone tropism observed in this triple negative breast cancer subtype.
By uncovering a mechanism linking tumour cell signalling to immune cell differentiation and bone destruction, the findings provide new insight into how bone metastases develop in triple negative breast cancer.
Reference
Liu Y et al. Androgen receptor interacts with c-Myc to regulate macrophage-osteoclast axis and drive bone metastasis in triple negative breast cancer. British Journal of Cancer. 2025;133:1776-90.
