Androgen receptor interacts with c-Myc to regulate macrophage-osteoclast axis and drive bone metastasis in triple negative breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metastasis Research

Background:

• Distant metastasis in breast cancer, including triple-negative breast cancer (TNBC), shows organotropism, but the underlying regulatory mechanisms are not fully understood.
• Understanding organ-specific metastasis in TNBC is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the organotropism of TNBC subtypes and elucidate the mechanisms of bone metastasis.
• To explore the role of the androgen receptor (AR) in TNBC bone metastasis.
• To identify key molecular interactions within the bone microenvironment that promote metastasis.

Main Methods:

• Retrospective analysis of metastatic data from public databases.
• In vivo studies using mouse models of TNBC bone metastasis.
• Single-cell sequencing, immunoprecipitation (CoIP), CUT&TAG sequencing, and osteoclast differentiation assays to analyze molecular mechanisms.

Main Results:

• The luminal androgen receptor (LAR) TNBC subtype demonstrated a significant propensity for bone metastasis.
• AR activation was found to promote LAR TNBC bone metastasis.
• AR-c-Myc interaction was identified as a key driver, promoting macrophage-osteoclast differentiation and activation via MMP13, leading to increased bone resorption.

Conclusions:

• The interaction between AR and c-Myc is a critical mechanism driving TNBC bone metastasis by inducing macrophage differentiation into osteoclasts.
• These findings provide novel insights into the molecular pathways governing bone metastasis in TNBC.
• The identified AR-c-Myc axis presents a potential therapeutic target for intervening in TNBC bone metastasis.