Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1055, New York, NY, 10029, USA.
Tisch Cancer Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Sci Rep. 2021 Sep 9;11(1):17927. doi: 10.1038/s41598-021-97327-y.
Expression of the low-density lipoprotein receptor (LDLR) has been shown to play a critical role in hypercholesterolemia-associated breast cancer growth and is associated with shorter recurrence-free survival in human breast cancer studies. We sought to identify how circulating LDL cholesterol and tumor LDLR might accelerate oncogenic processes by determining whether increased LDLR expression and cholesterol uptake are associated with the activation of the epidermal growth factor receptor (EGFR) signaling pathway in triple negative breast cancer (TNBC) cell lines. EGF stimulation of MDA-MB-468 (MDA468) cells activated p44/42MAPK (MAPK), increased expression of LDLR, and fluorescent LDL cholesterol uptake. However, stimulation of MDA-MB-231 (MDA231) cells with EGF did not lead to increased expression of LDLR despite inducing phosphorylation of EGFR. Inhibition of MAPK using UO126 in MDA231 cells reduced LDLR expression, and in MDA468 cells, UO126 impaired the LDLR increase in response to EGF. MDA468 cells exposed to the transcription inhibitor, Actinomycin, prior to treatment with EGF showed reduced degradation of LDLR mRNA compared to vehicle-treated cells. Our results suggest that the EGF-associated increase in LDLR protein expression is cell line-specific. The common pathway regulating LDLR expression was MAPK in both TNBC cell lines.
低密度脂蛋白受体（LDLR）的表达已被证明在高胆固醇血症相关的乳腺癌生长中发挥关键作用，并且与人类乳腺癌研究中无复发生存时间较短相关。我们试图通过确定循环 LDL 胆固醇和肿瘤 LDLR 是否通过增加 LDLR 表达和胆固醇摄取与三阴性乳腺癌（TNBC）细胞系中表皮生长因子受体（EGFR）信号通路的激活有关，来确定它们如何加速致癌过程。EGF 刺激 MDA-MB-468（MDA468）细胞激活 p44/42MAPK（MAPK），增加 LDLR 的表达，并摄取荧光 LDL 胆固醇。然而，EGF 刺激 MDA-MB-231（MDA231）细胞不会导致 LDLR 表达增加，尽管它诱导 EGFR 的磷酸化。在 MDA231 细胞中使用 UO126 抑制 MAPK 会降低 LDLR 的表达，而在 MDA468 细胞中，UO126 会损害 EGF 对 LDLR 增加的作用。与用载体处理的细胞相比，在用 EGF 处理之前用转录抑制剂放线菌素 D 处理的 MDA468 细胞中 LDLR mRNA 的降解减少。我们的结果表明，EGF 相关的 LDLR 蛋白表达增加是细胞系特异性的。两种 TNBC 细胞系中调节 LDLR 表达的共同途径是 MAPK。
