Lingrand Marine, Lalonde Simon, Jutras-Carignan Antoine, Bergeron Karl-F, Rassart Eric, Mounier Catherine
Molecular Metabolism of Lipids Laboratory, Biological Sciences Department, University of Quebec in Montreal (UQAM), 141 President-Kennedy Avenue, Montreal, QC, H2X 1Y4, Canada.
Breast Cancer. 2020 Jul;27(4):594-606. doi: 10.1007/s12282-020-01053-8. Epub 2020 Jan 29.
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).
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.
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.
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.
乳腺癌是女性中最常见的癌症。尽管西方国家的生存率较高，但治疗在转移性病例中效果较差，且三阴性乳腺癌（TNBC）患者的生存期在所有乳腺癌亚型中最短。据报道，硬脂酰辅酶A去饱和酶-1（SCD1）在乳腺癌中高表达。SCD1酶催化油酸（OA）的形成，油酸是一种刺激转移性乳腺癌细胞迁移的脂质。磷脂酶活性也与乳腺癌转移有关，尤其是磷脂酶D（PLD）。
利用基因表达数据库生成的Kaplan-Meier生存曲线分析SCD1和PLD在几种癌症亚型中的作用。在三种乳腺癌细胞系中，用药物抑制剂或OA处理（以模拟SCD1过度活性）来调节SCD1酶活性：TNBC来源的MDA-MB-231细胞以及非TNBC的MCF-7和T47D细胞。通过各种互补方法对细胞形态和迁移特性进行表征。
我们的生存分析表明，原发性肿瘤中SCD1和PLD2的表达均与乳腺癌患者转移相关的不良预后有关。我们表明，SCD1活性的调节与TNBC细胞迁移特性的改变有关，包括速度、方向和细胞形态的变化。细胞迁移特性通过PLD-mTOR/p70S6K信号通路受SCD1活性调节。在非TNBC细胞系中未观察到这些效应。
我们的结果确立了脂质去饱和酶SCD1的关键作用，并描绘了OA-PLD-mTOR/p70S6K信号通路在TNBC来源的MDA-MB-231细胞迁移中的作用。
