Androgen Receptor interacts with c-Myc to regulate macrophage-osteoclast axis and drive bone metastasis in Triple Negative Breast Cancer

Abstract Breast cancer distant metastasis is known to exhibit organotropism, with triple negative breast cancer (TNBC) subtypes also displaying organ-specific metastasis. In publicly available clinical database of TNBC, we found that luminal androgen receptor-type (LAR) TNBC had a significant tendency for bone metastasis. In mouse models, we demonstrated that androgen receptor (AR) activation promoted LAR TNBC bone metastasis. Using single-cell sequencing, we discovered that c-Myc played a critical role in AR-mediated bone metastasis. Mechanistically, AR interacted with c-Myc, promoting the expression of c-Myc and consequently facilitating TNBC osteolytic bone metastasis. Further analysis of the bone microenvironment revealed that AR interactions with c-Myc not only mediated macrophage M2 polarization, but also promoted M2-type macrophage differentiation towards osteoclasts as well as osteoclast activation, ultimately promoting bone resorption effects. Collectively, these findings elucidate the mechanisms underlying bone metastasis in TNBC subtypes and inform potential interventions for TNBC bone metastasis.