Cancer Research-UK Labs and Department of Surgery and Cancer, Hammersmith Campus, London W12 0NN, UK.
Curr Drug Targets. 2011 Aug;12(9):1256-66. doi: 10.2174/138945011796150244.
FOXO transcription factors, functioning downstream of the PI3K-PTEN-AKT (PKB) signalling cascade, are essential for cell proliferation, differentiation, DNA damage repair, and apoptosis. Recent research indicates that the related transcription factor FOXM1 is a direct target of repression by FOXO proteins. Inactivation of FOXO or overexpression of FOXM1 is associated with tumorigenesis and cancer progression. In addition, the cytostatic and cytotoxic effects of a diverse spectrum of anti-cancer drugs, such as paclitaxel, doxorubicin, lapatinib, gefitinib, imatinib, and cisplatin, are mediated through the activation of FOXO3a and/or the inhibition of its target FOXM1. Paradoxically, FOXO proteins also contribute to drug resistance by driving the expression of genes important for drug efflux as well as DNA repair and cell survival pathways in drug resistant cancers. Given its pivotal roles of in drug sensitivity as well as resistance, targeting the FOXO-FOXM1 axis could be a viable strategy for treatment of cancer and for overcoming drug resistance. Studying the expression profiles of the components of the FOXO-FOXM1 axis, and their cofactors, in cancer patients might also help to predict and monitor their clinical response to chemotherapy. A better understanding of the mechanism by which FOXO and FOXM1 are regulated, as well as their roles in drug sensitivity and resistance, may render these proteins crucial prognostic markers and therapeutic targets for breast cancer and other malignancies.
叉头框转录因子（FOXO transcription factors）是 PI3K-PTEN-AKT（PKB）信号级联途径下游的关键因子，对于细胞增殖、分化、DNA 损伤修复和细胞凋亡至关重要。最近的研究表明，相关转录因子 FOXM1 是 FOXO 蛋白直接抑制的靶标。FOXO 的失活或 FOXM1 的过表达与肿瘤发生和癌症进展有关。此外，多种抗癌药物，如紫杉醇、多柔比星、拉帕替尼、吉非替尼、伊马替尼和顺铂，通过激活 FOXO3a 和/或抑制其靶标 FOXM1 发挥细胞抑制和细胞毒性作用。矛盾的是，FOXO 蛋白也通过驱动药物外排以及耐药性癌症中 DNA 修复和细胞存活途径的基因表达，导致药物耐药。鉴于其在药物敏感性和耐药性方面的关键作用，靶向 FOXO-FOXM1 轴可能是治疗癌症和克服耐药性的可行策略。研究癌症患者 FOXO-FOXM1 轴的组成部分及其共因子的表达谱，也可能有助于预测和监测其对化疗的临床反应。更好地了解 FOXO 和 FOXM1 被调控的机制，以及它们在药物敏感性和耐药性方面的作用，可能使这些蛋白成为乳腺癌和其他恶性肿瘤的重要预后标志物和治疗靶点。
