Pathological and therapeutic implications of Notch overexpression in claudin-low breast cancers.

Claudin-low breast cancers (BCs), representing approximately 1.5-14% of all BCs, are characterized by high aggressiveness, enriched cancer stem cell (CSC) population, and poor prognosis. Despite the established role of Notch signaling in mammary gland development and BC progression, its status in claudin-low BCs remains inadequately explored. In this study, Notch pathway activation was evaluated in BC cell lines and 107 patient samples. Claudin-low subtype exhibited elevated Notch activity. Notch1 was observed to be the predominant receptor in the above subtype, whereas Notch3 was predominant in the claudin-high cancers. Notch1 and HES1 expression showed a significant inverse correlation with claudins 3, 4, and 7, and were positively associated with aggressive tumor features including high Ki67 index, higher grade, and increased metastasis. Immunohistochemical analysis further confirmed a correlation between nuclear Notch1 (N1ICD) expression and claudin-low status, supporting its potential as a biomarker for identification of aggressive BC. Combined treatment with celecoxib (10 µM) and doxorubicin (1 µM) in claudin-low cells not only significantly inhibited Notch signaling and claudin expression, but also suppressed viability, proliferation, migration, and BCSC populations. Since Notch signalling may be an essential factor in these latter events, our findings suggest that Notch1/N1ICD can serve as therapeutic targets for the better management of claudin-low BCs. However, validation of the same requires detailed functional studies involving modulation of each type of Notch receptor or other players involved in Notch signaling using more robust approaches.