脂肪酸合成增强是肿瘤细胞的一个标志性代谢改变。脂肪酸是合成细胞膜磷脂的基本原料，能为肿瘤细胞提供能量支持，还用于生成一系列促肿瘤脂质信号分子，对肿瘤的发生发展过程具有重要作用。硬脂酰辅酶A去饱和酶SCD1是催化饱和脂肪酸形成单不饱和脂肪酸的关键酶，是脂肪酸合成途径中最终步骤的限速酶。SCD1已被发现高表达于乳腺癌，可以催化油酸的形成，继而刺激乳腺癌细胞转移。磷脂酶活性也与乳腺癌转移密切相关，尤其磷脂酶PLD。
2020年1月29日，日本乳腺癌学会《乳腺癌》在线发表加拿大魁北克大学蒙特利尔分校的研究报告，探讨了SCD1和PLD对三阴性乳腺癌与非三阴性乳腺癌患者生存结局的影响及其具体机制。
该研究首先根据基因表达数据库生成的生存曲线，分析SCD1和PLD对三阴性乳腺癌与非三阴性乳腺癌患者生存结局的影响。随后，通过药物抑制剂或油酸（模拟SCD1过度活跃）对3种乳腺癌细胞株（三阴性乳腺癌MDA-MB-231细胞、非三阴性乳腺癌MCF-7和T47D细胞）SCD1的酶活性进行调节。最后通过各种补充方法对细胞形态和转移特征进行分析。
结果，生存分析表明，三阴性乳腺癌原发肿瘤的SCD1和PLD2表达水平，与三阴性乳腺癌患者的转移相关生存结局密切相关。调节SCD1活性，可以改变三阴性乳腺癌细胞转移特征，包括速度、方向和细胞形态的变化。通过PLD → mTOR → p70S6K信号通路，细胞转移特征受到SCD1活性的调节。对于非三阴性乳腺癌细胞株，未见上述作用。
因此，该研究结果表明，SCD1以及PLD → mTOR → p70S6K信号通路对于三阴性乳腺癌细胞转移具有关键作用，针对该靶点及其信号通路进行靶向治疗有望阻止三阴性乳腺癌发生转移。
Breast Cancer. 2020 Jan 29. [Epub ahead of print]
SCD1 activity promotes cell migration via a PLD-mTOR pathway in the MDA-MB-231 triple-negative breast cancer cell line.
Marine Lingrand, Simon Lalonde, Antoine Jutras-Carignan, Karl-F. Bergeron, Eric Rassart, Catherine Mounier.
University of Quebec in Montreal, Montreal, QC, Canada.
BACKGROUND: Breast cancer is the most common cancer in women. Despite high survival rates in Western countries, treatments are less effective in metastatic cases and triple-negative breast cancer (TNBC) patient survival is the shortest across breast cancer subtypes. High expression levels of stearoyl-CoA desaturase-1 (SCD1) have been reported in breast cancer. The SCD1 enzyme catalyzes the formation of oleic acid (OA), a lipid stimulating the migration of metastatic breast cancer cells. Phospholipase activity is also implicated in breast cancer metastasis, notably phospholipase D (PLD).
METHODS: Kaplan-Meier survival plots generated from gene expression databases were used to analyze the involvement of SCD1 and PLD in several cancer subtypes. SCD1 enzymatic activity was modulated with a pharmaceutical inhibitor or by OA treatment (to mimic SCD1 over-activity) in three breast cancer cell lines: TNBC-derived MDA-MB-231 cells as well as non-TNBC MCF-7 and T47D cells. Cell morphology and migration properties were characterized by various complementary methods.
RESULTS: Our survival analyses suggest that SCD1 and PLD2 expression in the primary tumor are both associated to metastasis-related morbid outcomes in breast cancer patients. We show that modulation of SCD1 activity is associated with the modification of TNBC cell migration properties, including changes in speed, direction and cell morphology. Cell migration properties are regulated by SCD1 activity through a PLD-mTOR/p70S6K signaling pathway. These effects are not observed in non-TNBC cell lines.
CONCLUSION: Our results establish a key role for the lipid desaturase SCD1 and delineate an OA-PLD-mTOR/p70S6K signaling pathway in TNBC-derived MDA-MB-231 cell migration.
KEYWORDS: Stearoyl-coenzyme A desaturase-1; Oleic acid; Phospholipase D; Mammalian target of rapamycin; Triple-negative breast cancer
DOI: 10.1007/s12282-020-01053-8
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