Beige Adipocytes Promote Triple‐Negative Breast Cancer Cell Migration and Malignancy Through BMP4 Signaling

Breast cancer remains a leading cause of cancer-related mortality among women, with adipocyte-breast cancer interactions playing a critical role in cancer progression. Mammary gland fat contains both white and brown-like adipocytes. While white adipocytes have been associated with aggressive tumor behavior, the impact of brown-like adipocytes on cancer progression remains largely unclear. This study investigated the roles of beige (UCP1^high) and white (UCP1^low) adipocytes derived from human adipose-derived mesenchymal stem cells within the tumor microenvironment. Triple-negative breast cancer (TNBC) MDA-MB-231 cells exhibited increased migration and invasion when exposed to white (hWCM) or beige (hBCM) adipocyte-conditioned medium, with a more pronounced effect observed with hBCM. Mechanistically, beige adipocytes secreted significantly higher levels of bone morphogenetic protein 4 (BMP4) compared to white adipocytes, which enhanced TNBC cell migration. Inhibition of BMP signaling with Noggin effectively reduced the migration and malignancy of MDA-MB-231 cells induced by hBCM, underscoring the pivotal role of BMP4 in breast cancer progression. Furthermore, an ex vivo model using primary mature adipocytes revealed that co-culturing MDA-MB-231 cells with UCP1^high adipocytes from cold-exposed mice increased cell migration and altered epithelial-mesenchymal transition gene expression compared to UCP1^low adipocytes from room temperature-housed mice. These findings highlight the critical role of UCP1^high beige adipocytes and BMP4 signaling in TNBC progression, suggesting that targeting BMP4 signaling may offer a novel therapeutic strategy for managing TNBC.