AIMS Opioids (i.e. morphine) were found to induce triple negative breast cancer (TNBC) metastasis while nonsteroidal anti-inflammatory drugs (i.e. ketolorac) were associated with decreased metastasis in TNBC. These contradictory findings demand clarification on the effect of postoperative morphine and ketorolac on TNBC metastasis. MATERIALS AND METHODS TNBC xenograft mice were established using MDA-MB-231 cells. When tumors reached ~100 mm3, the primary tumor was resected. Mice were then randomly assigned to four groups (n = 14): (i) saline, (ii) morphine (10 mg kg-1) (iii) morphine + ketorolac (10 mg kg-1 of morphine and 20 mg kg-1 of ketorolac) (iv) ketorolac (20 mg kg-1); administrated for three consecutive days after resection. Three weeks after resection, the number of lung metastases was measured. Microvessel density, thrombospondin-1 (TSP-1) and c-Myc expression in recurrent tumors were determined. To elucidate the above phenomenon in vitro, MDA-MB-231 cells were treated according to the regiment above; with or without supplementation of an AKT inhibitor to determine the activation of PI3K/AKT/c-Myc pathway. KEY FINDINGS In mice, morphine promoted TNBC metastasis and angiogenesis, decreased TSP-1 expression and increased c-Myc expression, while co-administration of ketorolac significantly reversed the phenotypes above (p < .05). Mechanistically, morphine inhibited TSP-1 secretion by activating PI3K/AKT/c-Myc pathway (p < .05), while ketorolac promoted TSP-1 secretion (p < .05) by suppressing PI3K/AKT/c-Myc pathway. SIGNIFICANCE Our study indicated that morphine enhanced TNBC metastasis and angiogenesis while ketorolac suppressed this effect. Mechanistically, this may be related to the enhancement of TSP-1 synthesis after ketorolac administration which further de-activated PI3K/AKT/c-Myc pathway.

中文翻译：

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术后服用酮咯酸可避免三阴性乳腺癌中吗啡诱导的血管生成和转移。

发现AIMS阿片类药物（即吗啡）可诱发三阴性乳腺癌（TNBC）转移，而非甾体类抗炎药（即酮洛拉克）与TNBC转移减少相关。这些矛盾的发现要求澄清术后吗啡和酮咯酸对TNBC转移的影响。材料与方法使用MDA-MB-231细胞建立TNBC异种移植小鼠。当肿瘤达到〜100 mm3时，将原发肿瘤切除。然后将小鼠随机分为四组（n = 14）：（i）盐水，（ii）吗啡（10 mg kg-1）（iii）吗啡+酮咯酸（10 mg kg-1吗啡和20 mg kg-1 （iv）酮咯酸（20 mg kg-1）；切除后连续三天给药。切除三周后，测量肺转移的数量。微血管密度 测定了复发性肿瘤中的血小板反应蛋白-1（TSP-1）和c-Myc表达。为了在体外阐明上述现象，按照上述方案处理MDA-MB-231细胞。是否添加AKT抑制剂来确定PI3K / AKT / c-Myc途径的激活。主要发现在小鼠中，吗啡促进了TNBC转移和血管生成，TSP-1表达降低和c-Myc表达增加，而酮咯酸的共同给药显着逆转了上述表型（p <.05）。从机理上讲，吗啡通过激活PI3K / AKT / c-Myc途径抑制TSP-1分泌（p <.05），而酮咯酸通过抑制PI3K / AKT / c-Myc途径促进TSP-1分泌（p <.05）。意义我们的研究表明吗啡可增强TNBC的转移和血管生成，而酮咯酸可抑制这种作用。