Notch-associated expression profiles in basal-like and claudin-low breast cancer molecular subtypes

Abstract

11017 Background: An attractive candidate target for breast cancer (BC) and BC tumor-initiating cells is the Notch signaling pathway. To better understand the potential dependence of breast cancer upon Notch-signaling, we used a genomic approach to study the activation of this pathway in the different molecular subtypes. Methods: Breast basal-like, luminal and HER2+ cell lines were examined for sensitivity to gamma-secretase inhibition (GSI). Gene expression data from the most sensitive cell line was analyzed during treatment and upon releasing from GSI (4h, 8h and 24h post-treatment). Using an unsupervised analysis, all time points were hierarchically clustered and genes that changed in expression were identified (SAM one-class). This Notch-associated signature identified in vitro was used to classify 2 distinct sporadic breast tumor populations (UNC and NKI, n=495). Each tumor sample was categorized into 6 molecular subtypes (basal-like, claudin-low [submitted], luminal A/B, HER2-enriched and normal-like). Results: In vitro, breast basal-like cell lines SUM102 and SUM149 were more sensitive to GSI (IC50, 0.3 and 1.5μM, respectively) compared to the luminal MCF7 (>10μM) and HER2+ SKBR3 (>5μM) cell lines. Over 340 genes that changed in expression (FDR<0.03%) were identified in SUM102, including known targets of the canonical Notch pathway (Hes1 and Hey2). Selected GO terms overrepresented in this signature were the following (EASE score, p<0.01): Wnt and Hedgehog signaling, embryonic development and cell differentiation. In vivo, 2 distinct gene clusters were evident in both populations, one of which was predictive of poor patient outcome. This Notch-associated poor prognostic signature was highly expressed in >90% of basal-like tumors. The second cluster was highly expressed in the recently identified claudin-low subtype, and was uniquely enriched with genes involved in cell differentiation (Sox7/9, Hey2, Dll1, Fzd5) and cell adhesion. Conclusions: Notch associated expression profiles are associated with basal-like and claudin-low BC subtypes, providing additional biological insight of pathway activation. GSI could represent a novel strategy for both subtypes, which represent the vast majority of the “triple negative” population. No significant financial relationships to disclose.