Author(s): Zhu H, Bhaijee F, Ishaq N, Pepper DJ, Backus K,
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Abstract Gene expression profiling reveals elevated Notch1 mRNA expression in triple negative breast cancers (TNBC), both basaloid and claudin-low subtypes. Notch ligands, Jagged1 and Jagged2, have been correlated with poor prognosis in TNBC. AKT, an oncogenic protein kinase family that is activated downstream of Notch in breast cancer cell lines, is frequently activated in breast cancer. Recent publications suggest that inhibition of cell growth, migration, invasion, and induction of apoptosis caused by Notch1 or Jagged1 inhibition may be attributed in part to inactivation of the AKT signaling pathway. There is significant evidence that Notch1 activates NF-κB in several models, and that AKT can mediate NF-κB activation. In this study, we evaluated Notch1 protein expression by immunohistochemistry (IHC) and correlated this with expression of pAKT and nuclear NF-κB p65 (RelA) in TNBC. A tissue microarray (TMA) containing 32 formalin-fixed, paraffin-embedded (FFPE) TNBC tumor specimens was constructed from the archival tissue database of the Department of Pathology at UMMC and IHC for Notch1 protein, pAKT 1/2/3 (Ser473), and NF-κB, p65 subunit was performed on the TMA with appropriate positive and negative controls. Of the 32 TNBC in our cohort, 100\% expressed Notch1 protein by IHC: 24 (75\%) showed cytoplasmic expression, 25 (78\%) showed membranous expression, and 17 (53\%) showed both cytoplasmic and membranous expression. Overall, 29 (91\%) expressed pAKT by IHC: 28 (97\%) showed cytoplasmic expression, 14 (48\%) showed nuclear expression and 13 (45\%) showed both cytoplasmic and nuclear expression. Nuclear staining for NF-κB p65 was detected in all 32 TNBC specimens with variable intensities. On bivariate analysis, cytoplasmic Notch1 was significantly correlated with cytoplasmic pAKT (r = 0.373, P = 0.035) and nuclear NF-κB (r = 0.483, P = 0.005); both cytoplasmic and nuclear pAKT significantly correlated with nuclear NF-κB (r = 0.391, P = 0.027; r = 0.525, P = 0.002, respectively). These results suggest that 1) the cross-talk between Notch1, AKT and NF-κB identified in preclinical models may operate in a significant fraction of human TNBC, and 2) combination therapy with agents targeting these pathways warrants further investigation.
This article was published in Am J Cancer Res
and referenced in Journal of Computer Science & Systems Biology