Chen Ying-Fang, Jiang Chung-Lin, Tan Chi-Ling, Lai Pei-Hsiang, Lin Fu-Jung
Department of Biochemical Science and Technology, National Taiwan University, Taipei, Taiwan.
Research Center for Development Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan.
FASEB J. 2025 May 15;39(9):e70557. doi: 10.1096/fj.202500158R.
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) and white (UCP1) 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 adipocytes from cold-exposed mice increased cell migration and altered epithelial-mesenchymal transition gene expression compared to UCP1 adipocytes from room temperature-housed mice. These findings highlight the critical role of UCP1 beige adipocytes and BMP4 signaling in TNBC progression, suggesting that targeting BMP4 signaling may offer a novel therapeutic strategy for managing TNBC.
乳腺癌仍然是女性癌症相关死亡的主要原因，脂肪细胞与乳腺癌的相互作用在癌症进展中起着关键作用。乳腺脂肪中含有白色和棕色样脂肪细胞。虽然白色脂肪细胞与侵袭性肿瘤行为有关，但棕色样脂肪细胞对癌症进展的影响仍 largely 不清楚。本研究调查了肿瘤微环境中源自人脂肪间充质干细胞的米色（UCP1）和白色（UCP1）脂肪细胞的作用。三阴性乳腺癌（TNBC）MDA-MB-231 细胞在暴露于白色（hWCM）或米色（hBCM）脂肪细胞条件培养基时，迁移和侵袭增加，hBCM 的作用更明显。机制上，与白色脂肪细胞相比，米色脂肪细胞分泌的骨形态发生蛋白 4（BMP4）水平显著更高，这增强了 TNBC 细胞的迁移。用 Noggin 抑制 BMP 信号有效地降低了 hBCM 诱导的 MDA-MB-231 细胞的迁移和恶性程度，强调了 BMP4 在乳腺癌进展中的关键作用。此外，使用原代成熟脂肪细胞的体外模型显示，与来自室温饲养小鼠的 UCP1 脂肪细胞相比，将 MDA-MB-231 细胞与来自冷暴露小鼠的 UCP1 脂肪细胞共培养可增加细胞迁移并改变上皮-间质转化基因表达。这些发现突出了 UCP1 米色脂肪细胞和 BMP4 信号在 TNBC 进展中的关键作用，表明靶向 BMP4 信号可能为 TNBC 的治疗提供一种新的策略。
