Inhibition of HER2 Increases JAGGED1-dependent Breast Cancer Stem Cells: Role for Membrane JAGGED1

Abstract

<b>Purpose:</b> HER2-positive breast cancer is driven by cells possessing stem-like properties of self-renewal and differentiation, referred to as cancer stem cells (CSC). CSCs are implicated in radiotherapy, chemotherapy resistance, and tumor recurrence. NOTCH promotes breast CSC survival and self-renewal, and overexpression of NOTCH1 and the NOTCH ligand JAGGED1 predict poor outcome. Resistance to anti-HER2 therapy in HER2⁺ breast cancer requires NOTCH1, and that combination of trastuzumab and a gamma secretase inhibitor (GSI) prevents tumor relapse in xenograft models.<b>Experimental Design:</b> The current study investigates mechanisms by which HER2 tyrosine kinase activity regulates NOTCH-dependent CSC survival and tumor initiation.<b>Results:</b> Lapatinib-mediated HER2 inhibition shifts the population of HER2⁺ breast cancer cells from low membrane JAGGED1 expression to higher levels, independent of sensitivity to anti-HER2 treatment within the bulk cell population. This increase in membrane JAGGED1 is associated with higher NOTCH receptor expression, activation, and enrichment of CSCs <i>in vitro</i> and <i>in vivo</i> Importantly, lapatinib treatment results in growth arrest and cell death of JAGGED1 low-expressing cells while the JAGGED1 high-expressing cells continue to cycle. High membrane JAGGED1 protein expression predicts poor overall cumulative survival in women with HER2⁺ breast cancer.<b>Conclusions:</b> These results indicate that higher membrane JAGGED1 expression may be used to either predict response to anti-HER2 therapy or for detection of NOTCH-sensitive CSCs posttherapy. Sequential blockade of HER2 followed by JAGGED1 or NOTCH could be more effective than simultaneous blockade to prevent drug resistance and tumor progression. <i>Clin Cancer Res; 24(18); 4566-78. ©2018 AACR</i>.