Considerable evidence suggests that as breast cancer progresses, genetic and epigenetic mechanisms contribute to the emergence of self-renewing cells (CSC), which may also arise as a consequence of metastasis. Although the molecular pathways that trigger stemness and metastasis are known, key molecular and mechanistic gaps in our understanding of these processes remain unclear. Here, we first screened the inflammation-associated stemness gene phosphodiesterase 3A (PDE3A) using a medium-throughput siRNA library, which was overexpressed in breast tumors and significantly correlated with clinical progression. PDE3A induced the inflammatory nuclear factor NFκB signaling pathway by suppressing cAMP/PKA, which promotes the expression of the stem cell marker OCT4. In addition, PDE3A also promoted the translocation of CCDC88A from the cytoplasm to nuclei, thereby boosting the invasion–metastasis cascade in breast cancer. Most importantly, the PDE3A-selective inhibitor cilostazol dramatically suppressed breast tumor growth and reduced metastasis to the lungs in xenograft breast cancer models, with minimum toxicity. Taken together, we show that PDE3A could predispose patients with breast cancer to metastases by acting as a mediator of cancer stemness. PDE3A is a potential therapeutic target for advanced breast cancer.

中文翻译：

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磷酸二酯酶 3A 是一种治疗靶点，可驱动乳腺癌的干细胞样特性和转移

大量证据表明，随着乳腺癌的进展，遗传和表观遗传机制有助于自我更新细胞 (CSC) 的出现，这也可能是转移的结果。尽管触发干性和转移的分子途径是已知的，但我们对这些过程的理解中的关键分子和机制差距仍不清楚。在这里，我们首先使用中等通量的 siRNA 文库筛选了炎症相关的干细胞基因磷酸二酯酶 3A (PDE3A)，该文库在乳腺肿瘤中过度表达并与临床进展显着相关。PDE3A 通过抑制 cAMP/PKA 来诱导炎性核因子 NFκB 信号通路，从而促进干细胞标志物 OCT4 的表达。此外，PDE3A 还促进了 CCDC88A 从细胞质向细胞核的易位，从而促进乳腺癌的侵袭转移级联反应。最重要的是，在异种移植乳腺癌模型中，PDE3A 选择性抑制剂西洛他唑显着抑制了乳腺肿瘤的生长并减少了向肺部的转移，且毒性最小。综上所述，我们表明 PDE3A 可以作为癌症干性的介质，使乳腺癌患者易发生转移。PDE3A 是晚期乳腺癌的潜在治疗靶点。我们表明 PDE3A 可以通过充当癌症干细胞的介质使乳腺癌患者易发生转移。PDE3A 是晚期乳腺癌的潜在治疗靶点。我们表明 PDE3A 可以通过充当癌症干细胞的介质使乳腺癌患者易发生转移。PDE3A 是晚期乳腺癌的潜在治疗靶点。