Notch Signaling Pathway: An Emerging Therapeutic Target for African-American Triple Negative Breast Cancer Patients

Abstract

The most fatal form of breast cancer, triple negative (TNBC), continues to challenge clinicians worldwide with its lack of reliable prognostic biomarkers and pharmacologically actionable treatment targets. In the US, this aggressive disease disproportionately afflicts African-American (AA) women at a rate 2-3 times higher than European-American (EA) women, thereby contributing to the observed higher mortality rates of AA BC patients.  In order to address the unmet clinical need for new and effective treatments for AA TNBCs, we describe herein a potentially actionable pathway that appears to be in overdrive in TNBCs of AA patients compared to EA TNBCs: the Notch signaling pathway. Notch signaling is implicated in multiple aspects of carcinogenesis and tumor progression including in regulation of proliferation, apoptosis, the biology of cancer stem cells, tumor angiogenesis and epithelial-to-mesenchymal transition. Our gene expression analyses uncover significant upregulation of Notch signaling as well as gene ontologies reflecting dysregulation of key processes regulated by Notch signaling among AA compared to EA TNBC patients. Furthermore, we present evidence suggesting that upregulated Notch signaling may predict poor prognosis in TNBC. Our findings thus suggest differences in Notch signaling among racially-distinct TNBC patients that may contribute to the more aggressive clinical behavior of TNBC in AAs. These observations also suggest that Notch signaling may be an attractive therapeutic target for high-risk AA TNBC patients.