Evaluation of liver kinase B1 downstream signaling expression in various breast cancers and relapse free survival after systemic chemotherapy treatment.

Nguyen Khoa,Yousefi Hassan,Matossian Margarite,Alahari Suresh,Collins-Burow Bridgette,Wathieu Henri,Drewry David,Alzoubi Madlin,Dong Shengli,Rivera Andrew,Burow Matthew

doi:10.18632/oncotarget.27929

Abstract

LKB1-signaling has prominent roles in cancer development and metastasis. This report evaluates LKB1-signaling pathway gene expression associations with patient survival in overall breast cancer, specific subtypes, as well as pre- and post-chemotherapy. Subtypes analyzed were based on intrinsic molecular subtyping and traditional biomarker classifications. Intrinsic molecular subtypes included were Luminal-A, Luminal-B, HER2-enriched, and Basal-like. The biomarker subtypes assessed were Estrogen-Receptor Positive (ER+) and Negative (ER-), Wild-Type TP53 (WT-TP53) & Mutant-TP53, and Triple-Negative Breast Cancer (TNBC). Additionally, comparisons were made between these subtypes and breast cancer overall, and analyses between LKB1 signaling to patient survival before and after chemotherapy were made. We used the Kaplan-Meier Online Tool (KM Plotter) to correlate the relationship between mRNA expression of known LKB1 scaffolding proteins (CAB39 and LYK5), and downstream signaling targets (AMPK, MARK1, MARK2, MARK3, MARK4, NUAK1, NUAK2, PAK1, SIK1, SIK2, BRSK1, BRSK2, SNRK, and QSK), and patient survival across each subtype and treatment group. Our findings provide evidence that LKB1-signaling is associated with improved survival in overall breast cancer. Stratification into breast cancer subtypes show a more complicated relationship; NUAK2, for example, is correlated with improved survival in ER- but is worse in ER+ breast cancer. In evaluating the association of LKB1-signaling pathway expression with relapse free survival of varying breast cancer tumors exposed to chemotherapy or treatment-naive tumors, our data provides baseline knowledge for understanding the pathway dynamics that affect survival and therefore are linked to pathology. This establishes a foundation for studying LKB1 targets with the goal of identifying druggable targets.

Highlights

Liver kinase B1 (LKB1), known as STK11, is a ubiquitously expressed master serine/threonine kinase that has been demonstrated to have tumor suppressing activity
This report seeks to fill that gap by identifying correlations between members of LKB1 signaling with patient outcomes in different breast cancer subtypes pre- and post-chemotherapy
Genes associated with increased survival were LKB1, AMPK, LYK5, MARK1, MARK2, NUAK2, PAK1, SIK1, SIK2, BRSK1, BRSK2, SNRK, and QSK

Summary

Introduction

Liver kinase B1 (LKB1), known as STK11, is a ubiquitously expressed master serine/threonine kinase that has been demonstrated to have tumor suppressing activity. It plays integral roles in many cancer processes with functionally broad roles in controlling cell polarity, proliferation, differentiation, and metabolism [1, 2]. Despite the current literature on LKB1 signaling in different diseases, its role in breast cancer remains understudied. This report seeks to fill that gap by identifying correlations between members of LKB1 signaling with patient outcomes in different breast cancer subtypes pre- and post-chemotherapy. The ultimate goal of this report is to establish a baseline for clinical applications of targeted therapy, with results from intrinsic subtyping, while establishing a foundation for basic science pursuits with results from biomarker-based grouping

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