Acquisition of Letrozole Resistance Through Activation of the P38/MAPK Signaling Cascade

Overview

Journal Anticancer Res

Specialty Oncology

Date 2021 Jan 31

PMID 33517263

Citations 4

Authors

Rashidra R Walker

Karen M Gallegos

Melyssa R Bratton

Kitani P Lemieux

Kun Zhang

Guangdi Wang

A Michael Davidson

Syreeta L Tilghman

Affiliations

Soon will be listed here.

Abstract

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+).

Materials And Methods: 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.

Results: 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.

Conclusion: Activation of the p38/MAPK pathway leads to ER+ AI-resistance.

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The genomic landscape associated with resistance to aromatase inhibitors in breast cancer.

Sadasivam K, Manoharan J, Palanisamy H, Vidyalakshmi S Genomics Inform. 2023; 21(2):e20.

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