Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia.
School of Cancer Medicine, La Trobe University, Bundoora, VIC 3083, Australia.
Int J Mol Sci. 2024 Aug 23;25(17):9160. doi: 10.3390/ijms25179160.
We reported previously that in preclinical models, BMP4 is a potent inhibitor of breast cancer metastasis and that high BMP4 protein levels predict favourable patient outcomes. Here, we analysed a breast cancer xenograft with or without enforced expression of BMP4 to gain insight into the mechanisms by which BMP4 suppresses metastasis. Transcriptomic analysis of cancer cells recovered from primary tumours and phosphoproteomic analyses of cancer cells exposed to recombinant BMP4 revealed that BMP4 inhibits cholesterol biosynthesis, with many genes in this biosynthetic pathway being downregulated by BMP4. The treatment of mice bearing low-BMP4 xenografts with a cholesterol-lowering statin partially mimicked the anti-metastatic activity of BMP4. Analysis of a cohort of primary breast cancers revealed a reduced relapse rate for patients on statin therapy if their tumours exhibited low BMP4 levels. These findings indicate that BMP4 may represent a predictive biomarker for the benefit of additional statin therapy in breast cancer patients.
我们之前曾报道称，在临床前模型中，BMP4 是一种有效的乳腺癌转移抑制剂，并且 BMP4 蛋白水平高预示着患者预后良好。在这里，我们分析了一个带有或不带有强制表达 BMP4 的乳腺癌异种移植物，以深入了解 BMP4 抑制转移的机制。从原发肿瘤中回收的癌细胞的转录组分析和暴露于重组 BMP4 的癌细胞的磷酸化蛋白质组学分析表明，BMP4 抑制胆固醇生物合成，该生物合成途径中的许多基因被 BMP4 下调。用降低胆固醇的他汀类药物治疗低 BMP4 异种移植物的小鼠部分模拟了 BMP4 的抗转移活性。对一组原发性乳腺癌的分析显示，如果肿瘤中 BMP4 水平较低，接受他汀类药物治疗的患者的复发率降低。这些发现表明，BMP4 可能是预测乳腺癌患者是否从额外的他汀类药物治疗中获益的生物标志物。
