Cholesterol Enhances Breast Cancer Progression Through PI3K-Independent Akt Activation.

Emerging evidence suggests cholesterol plays a crucial role in cancer development, yet the specific molecular mechanisms connecting cholesterol to cancer progression remain unclear. The study described in this thesis reveals that a higher level of cholesterol accumulates in the inner leaflet of the plasma membrane (IPM) in breast cancer cells compared to normal cells. For example, in inflammatory breast cancer (IBC) cells, the IPM cholesterol level is significantly higher than in primary mammary cells. This elevated cholesterol directly interacts with the Pleckstrin homology (PH) domain of Akt1 and Akt2, leading to their translocation and activation, which is independent of Class I phosphoinositide 3-kinase (PI3K). The cholesterol-induced activation of Akt regulates all known major downstream signaling pathways. Unlike PI3K-activated Akt, cholesterol-activated Akt exhibit kinase-independent scaffolding activity, which is crucial for the phosphorylation of GSK3α and FoxO3a, enhancing cell proliferation, survival, and treatment resistance. A specific small molecule inhibitor EJK3-7 was found to effectively block cholesterol-mediated activation of Akt and its scaffolding activity. EJK3-7 significantly inhibites the PI3K-independent oncogenic activity of IBC cells, which conventional Akt inhibitors could not achieve. Importantly, EJK3-7 did not affect the canonical PI3K-Akt signaling in normal mammary cells. These findings suggest a previously unknown mechanism that links the role of cholesterol to breast cancer progression and treatment resistance. This new role of cholesterol can be exploited for developing a novel therapeutic approach targeting cholesterol-mediated oncogenic signaling, which will be advantages over treatments targeting cholesterol biosynthesis or traditional kinase inhibitor treatments.