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Current treatment of triple negative breast cancer is hindered by a high incidence of chemoresistance (30-50%). The prevailing theory is that resistance and subsequent recurrence is driven by cancer stem cells. Unfortunately, the functional characterization of cancer stem cells at the molecular level is still incomplete. We show here, that within the canonical breast cancer stem cell population (CD24low/CD44+/ESA+) of triple negative breast cancer cells, a subset of cells characterized by high Notch1 expression possesses the tumor-initiating and chemoresistance properties associated with cancer stem cells. Moreover, the tumor initiating property of these Notch1-high expressing breast cancer stem cells is mediated by the repression of SIRT1. We also demonstrate that Notch1 represses SIRT1 through a non-canonical, cleavage independent pathway via PI3K/Akt/mTORC2. Strikingly, the repression of SIRT1 obviates the requirement for high Notch1 expression. These findings provide the first functional mechanistic requirements for breast cancer stem cell tumor initiation and chemoresistance. Our results also identify a novel non-canonical Notch1 signaling pathway regulating breast cancer stem cell function. We postulate that this pathway can be exploited as a potential therapeutic strategy to eradicate cancer stem cells and reduce the incidence of chemoresistance and recurrence. Citation Format: Lufei Sui, Suming Wang, Danielle Sim, Randolph S. Watnick. Notch1 non-canonical pathway drives breast cancer stem cell function [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4963.