Dual Mechanisms of LYN Kinase Dysregulation Drive Aggressive Behavior in Breast Cancer Cells

Giusy Tornillo,Catherine Knowlson,Howard Kendrick,Joe Cooke,Hasan Mirza,Iskander Aurrekoetxea-Rodríguez,Maria D.M Vivanco,Niamh E Buckley,Anita Grigoriadis,Matthew J Smalley

doi:10.1016/j.celrep.2018.11.103

Abstract

SummaryThe SRC-family kinase LYN is highly expressed in triple-negative/basal-like breast cancer (TNBC) and in the cell of origin of these tumors, c-KIT-positive luminal progenitors. Here, we demonstrate LYN is a downstream effector of c-KIT in normal mammary cells and protective of apoptosis upon genotoxic stress. LYN activity is modulated by PIN1, a prolyl isomerase, and in BRCA1 mutant TNBC PIN1 upregulation activates LYN independently of c-KIT. Furthermore, the full-length LYN splice isoform (as opposed to the Δaa25–45 variant) drives migration and invasion of aggressive TNBC cells, while the ratio of splice variants is informative for breast cancer-specific survival across all breast cancers. Thus, dual mechanisms—uncoupling from upstream signals and splice isoform ratios—drive the activity of LYN in aggressive breast cancers.

Highlights

Breast cancers molecularly classified as basal-like breast cancer typically display the triple (ER/PR/HER2)-negative (TNBC) phenotype (Badve et al, 2011)
LYN Kinase Is Regulated by c-KIT and Promotes Growth of Normal Mammary Epithelial Cells To define the major components of the c-KIT signaling network in the mammary epithelium, we examined expression of c-KIT and its ligand stem cell factor (SCF) in normal mouse mammary cell populations (Figure 1A)
The two SCF isoforms, soluble SCF and membrane-bound SCF, were present at low levels in luminal cells, whereas basal cells showed the highest levels of total SCF, with almost exclusive expression of the sSCF form (Figures 1B and 1C)

Summary

Introduction

Breast cancers molecularly classified as basal-like breast cancer typically display the triple (ER/PR/HER2)-negative (TNBC) phenotype (Badve et al, 2011). The molecular etiology of sporadic TNBC is still poorly understood, germline BRCA1 mutations predispose to TNBC, and BRCA1 silencing or dysfunction in the BRCA1 pathway can be found in sporadic TNBC (Badve et al, 2011). The mammary epithelium consists of luminal cells, including ER-negative (ERÀ) progenitor-like and ER-positive (ER+) differentiated cells, and basal cells. TNBC likely originates from luminal ERÀ progenitors, and the gene expression profile of both BRCA1 mutation-associated and sporadic TNBC reflects a luminal progenitor-like profile (Lim et al, 2009; Molyneux et al, 2010).

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Conclusion