Division of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, U.S.A.
Biospecimens Core Laboratory, Louisiana Cancer Research Center, New Orleans, LA, U.S.A.
Anticancer Res. 2021 Feb;41(2):583-599. doi: 10.21873/anticanres.14810.
BACKGROUND/AIM: Previous reports identified a global proteomic signature of estrogen-independent letrozole resistant breast cancer cells, however, it remains unclear how letrozole-resistance is impacted when cells remain estrogen receptor positive (ER+).
To capture the protein expression profile associated with ER+ Aromatase inhibitor (AI) resistance, a global proteomic analysis was conducted using the letrozole-sensitive (T47Darom cells) and letrozole-resistant cells (T47DaromLR cells). To examine the molecular features associated with this phenotype Kaplan- Meier analysis, phospho-antibody arrays, proliferation and apoptosis assays were conducted.
MAP3K6 was up-regulated in the T47DaromLR cells by 3.2-fold (p<0.01) which was associated with a decrease in relapse-free survival among breast cancer patients (p=0.0019). Members of the MAPK/p38 pathway (i.e., phospho-MKK6, phospho-p38, phospho-RSK1, phospho-RSK2, and p70S6K MAPK) were also increased in the T47DaromLR cells, while inhibiting p38 led to decreased proliferation and induction of apoptosis.
Activation of the p38/MAPK pathway leads to ER+ AI-resistance.
背景/目的：先前的报告确定了雌激素非依赖性来曲唑耐药乳腺癌细胞的全局蛋白质组学特征，然而，当细胞仍然为雌激素受体阳性（ER+）时，来曲唑耐药性如何受到影响仍不清楚。
为了捕获与 ER+芳香酶抑制剂（AI）耐药相关的蛋白质表达谱，使用来曲唑敏感（T47Darom 细胞）和来曲唑耐药细胞（T47DaromLR 细胞）进行了全局蛋白质组学分析。为了研究与该表型相关的分子特征，进行了 Kaplan-Meier 分析、磷酸化抗体阵列、增殖和凋亡测定。
MAP3K6 在 T47DaromLR 细胞中上调 3.2 倍（p<0.01），这与乳腺癌患者无复发生存率降低相关（p=0.0019）。MAPK/p38 途径的成员（即磷酸化 MKK6、磷酸化 p38、磷酸化 RSK1、磷酸化 RSK2 和 p70S6K MAPK）在 T47DaromLR 细胞中也增加，而抑制 p38 导致增殖减少和凋亡诱导。
p38/MAPK 途径的激活导致 ER+AI 耐药。
