Metastasis is the major cause of death in cancer patients; with no therapeutic cure, treatments remain largely palliative. As such, new targets and therapeutic strategies are urgently required. Here we show that bone morphogenetic protein-4 (BMP4) blocks metastasis in animal models of breast cancer and predicts improved survival in patients. In preclinical models of spontaneous metastasis, BMP4 acted as an autocrine mediator to modulate a range of known metastasis-regulating genes, including SMAD7, via activation of canonical BMP-SMAD signaling. Restored BMP4 expression, or therapeutically administered BMP4 protein, blocked metastasis and increased survival by sensitising cancer cells to anoikis, thereby reducing the number of circulating tumour cells. Gene silencing of BMP4, or its downstream mediator SMAD7, reversed this phenotype. Administration of recombinant BMP4 markedly reduced spontaneous metastasis to lung and bone. Elevated levels of BMP4 and SMAD7 were prognostic for improved recurrence-free survival and overall survival in breast cancer patients, indicating the importance of canonical BMP4 signaling in the suppression of metastasis and highlighting new avenues for therapy against metastatic disease.

中文翻译：

---

规范的BMP4-SMAD7信号的激活抑制了乳腺癌的转移。

转移是癌症患者死亡的主要原因。在没有治疗方法的情况下，治疗仍在很大程度上姑息治疗。因此，迫切需要新的靶标和治疗策略。在这里，我们显示骨形态发生蛋白4（BMP4）阻止乳腺癌动物模型中的转移，并预测患者生存期的改善。在自发转移的临床前模型中，BMP4充当自分泌介体，通过激活典型BMP-SMAD信号传导来调节一系列已知的转移调节基因，包括SMAD7。恢复的BMP4表达或治疗性施用的BMP4蛋白通过使癌细胞对神经过敏敏感，从而阻止了转移并提高了生存率，从而减少了循环肿瘤细胞的数量。BMP4或其下游介质SMAD7的基因沉默逆转了该表型。重组BMP4的使用显着降低了自发转移至肺和骨的能力。BMP4和SMAD7的水平升高预后可改善乳腺癌患者的无复发生存率和总体生存率，表明规范的BMP4信号传导在抑制转移中的重要性，并突出了治疗转移性疾病的新途径。