The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer.
The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer.
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DOI：
10.1038/oncsis.2015.16
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发表时间：
2015-06-08
期刊：
影响因子：
6.2
通讯作者：
Spiegel S
中科院分区：
文献类型：
--
作者：
Hait NC;Avni D;Yamada A;Nagahashi M;Aoyagi T;Aoki H;Dumur CI;Zelenko Z;Gallagher EJ;Leroith D;Milstien S;Takabe K;Spiegel S
雌激素受体-α（ERα）阴性乳腺癌在临床上具有侵袭性，对常规激素治疗无反应。导致ERα再表达的策略可以使ERα阴性乳腺癌对选择性ER调节剂敏感。FTY 720（芬戈莫德，Gilenya），一种鞘氨醇类似物，是食品和药物管理局（FDA）批准的用于治疗多发性硬化症的前药，其也具有尚未充分理解的抗癌作用。我们发现FTY 720在乳腺癌细胞中被核鞘氨醇激酶2磷酸化并在那里积累。核FTY 720-P是I类组蛋白去乙酰化酶（HDAC）的有效抑制剂，其增强组蛋白乙酰化并调节一组受限基因的表达，独立于其对通过鞘氨醇-1-磷酸受体的典型信号传导的已知作用。高脂饮食（HFD）和肥胖，这是现在流行，增加乳腺癌的风险，并已与预后较差。在MMTV-PyMT转基因小鼠中，HFD加速了具有更晚期病变的肿瘤的发病，并增加了三阴性自发性乳腺肿瘤和HDAC活性。口服临床相关剂量的FTY 720抑制这些小鼠中自发性乳腺肿瘤的发展、进展和侵袭性，降低HDAC活性，并显著逆转HFD诱导的晚期癌中雌激素和孕激素受体的丧失。在ERα阴性的人和小鼠乳腺癌细胞中，FTY 720重新激活沉默的ERα的表达，并使它们对他莫昔芬敏感。此外，FTY 720治疗还重新表达ERα，并增加ERα阴性同基因乳腺肿瘤对他莫昔芬的治疗敏感性，其效力高于已知的HDAC抑制剂。我们的工作表明，FTY 720的多管齐下的攻击是一种有效治疗传统激素治疗抵抗性乳腺癌和三阴性乳腺癌的新组合方法。
Estrogen receptor-α (ERα)-negative breast cancer is clinically aggressive and does not respond to conventional hormonal therapies. Strategies that lead to re-expression of ERα could sensitize ERα-negative breast cancers to selective ER modulators. FTY720 (fingolimod, Gilenya), a sphingosine analog, is the Food and Drug Administration (FDA)-approved prodrug for treatment of multiple sclerosis that also has anticancer actions that are not yet well understood. We found that FTY720 is phosphorylated in breast cancer cells by nuclear sphingosine kinase 2 and accumulates there. Nuclear FTY720-P is a potent inhibitor of class I histone deacetylases (HDACs) that enhances histone acetylations and regulates expression of a restricted set of genes independently of its known effects on canonical signaling through sphingosine-1-phosphate receptors. High-fat diet (HFD) and obesity, which is now endemic, increase breast cancer risk and have been associated with worse prognosis. HFD accelerated the onset of tumors with more advanced lesions and increased triple-negative spontaneous breast tumors and HDAC activity in MMTV-PyMT transgenic mice. Oral administration of clinically relevant doses of FTY720 suppressed development, progression and aggressiveness of spontaneous breast tumors in these mice, reduced HDAC activity and strikingly reversed HFD-induced loss of estrogen and progesterone receptors in advanced carcinoma. In ERα-negative human and murine breast cancer cells, FTY720 reactivated expression of silenced ERα and sensitized them to tamoxifen. Moreover, treatment with FTY720 also re-expressed ERα and increased therapeutic sensitivity of ERα-negative syngeneic breast tumors to tamoxifen in vivo more potently than a known HDAC inhibitor. Our work suggests that a multipronged attack with FTY720 is a novel combination approach for effective treatment of both conventional hormonal therapy-resistant breast cancer and triple-negative breast cancer.