TGFβ signaling promotes progression of bone-metastatic (BMET) breast cancer (BCa) cells by driving tumor-associated osteolysis, a hallmark of BCa BMETs, thus allowing for tumor expansion within bone. Turmeric-derived bioactive curcumin, enriched in bone via local enzymatic deconjugation of inactive circulating curcumin-glucuronides, inhibits osteolysis and BMET progression in human xenograft BCa BMET models by blocking tumoral TGFβ signaling pathways mediating osteolysis. This is a unique antiosteolytic mechanism in contrast to current osteoclast-targeting therapeutics. Therefore, experiments were undertaken to elucidate the mechanism for curcumin inhibition of BCa TGFβ signaling and the application of this finding across multiple BCa cell lines forming TGFβ-dependent BMETs, including a possible role for bioactive curcumin metabolites in mediating these effects. Immunoblot analysis of TGFβ signaling proteins in bone tropic human (MDA-SA, MDA-1833, MDA-2287) and murine (4T1) BCa cells revealed uniform curcumin blockade of TGFβ-induced Smad activation due to down-regulation of plasma membrane associated TGFβR2 and cellular receptor Smad proteins that propagate Smad-mediated gene expression, resulting in downregulation of PTHrP expression, the osteolytic factor driving in vivo BMET progression. With the exception of early decreases in TGFβR2, inhibitory effects appeared to be mediated by oxidative metabolites of curcumin and involved inhibition of gene expression. Interestingly, while not contributing to changes in Smad-mediated TGFβ signaling, curcumin caused early activation of MAPK signaling in all cell lines, including JNK, an effect possibly involving interactions with TGFβR2 within lipid rafts. Treatment with curcumin or oxidizable analogs of curcumin may have clinical relevancy in the management of TGFβ-dependent BCa BMETs.

TGFβ 信号传导通过驱动肿瘤相关骨溶解（BCa BMET 的标志）来促进骨转移 (BMET) 乳腺癌 (BCa) 细胞的进展，从而允许肿瘤在骨内扩张。姜黄衍生的生物活性姜黄素通过无活性的循环姜黄素-葡萄糖苷酸的局部酶解结合而在骨中富集，通过阻断介导骨溶解的肿瘤 TGFβ 信号通路，抑制人异种移植 BCa BMET 模型中的骨溶解和 BMET 进展。与目前的破骨细胞靶向疗法相比，这是一种独特的抗骨质溶解机制。因此，我们进行了实验来阐明姜黄素抑制 BCa TGFβ 信号传导的机制，以及这一发现在形成 TGFβ 依赖性 BMET 的多种 BCa 细胞系中的应用，包括生物活性姜黄素代谢物在介导这些作用中的可能作用。对骨向性人 (MDA-SA、MDA-1833、MDA-2287) 和鼠 (4T1) BCa 细胞中 TGFβ 信号蛋白的免疫印迹分析显示，由于质膜相关 TGFβR2 下调，姜黄素均能阻断 TGFβ 诱导的 Smad 激活细胞受体 Smad 蛋白传播 Smad 介导的基因表达，导致 PTHrP 表达下调，PTHrP 是驱动体内BMET 进展的溶骨因子。除了 TGFβR2 的早期降低外，抑制作用似乎是由姜黄素的氧化代谢物介导的，并涉及基因表达的抑制。有趣的是，虽然姜黄素不会导致 Smad 介导的 TGFβ 信号传导发生变化，但它会导致包括 JNK 在内的所有细胞系中 MAPK 信号传导的早期激活，这种效应可能涉及与脂筏内 TGFβR2 的相互作用。姜黄素或姜黄素可氧化类似物的治疗可能在 TGFβ 依赖性 BCa BMET 的治疗中具有临床相关性。