UC Berkeley

The first known documentation of breast cancer comes from an Egyptian transcript that is over 4,000 years old. In this document, the physician Imhotep provided detailed descriptions of breast tumors and stated, "for a treatment, there is none." Today, breast cancer remains incurable and continues to be a major disease affecting women. Cancer stem cells are a subpopulation within solid tumors that drive tumor growth due to their ability to self-renew, initiate tumors, and resist treatment. The characteristics of cancer stem cells are influenced by various signaling pathways, which have significant links to the polarity of epithelial cells.

Polarity is essential for the spatial organization of signaling pathways within cells. Polarity proteins help regulate signal transduction across a diverse range of cellular processes. One critical membrane-bound polarity protein is SCRIB, which maintains the basolateral membrane domain. When SCRIB is mislocalized to the cytosol, it promotes mammary tumor development. SCRIB interacts significantly with the Hippo signaling pathway, which is responsible for regulating tissue growth, organ size, and stem cell fate. The interaction between SCRIB-dependent cell polarity and the Hippo pathway affects the activity of the Hippo effector, TAZ. Oncogenic TAZ is often highly expressed in breast cancer, and its activity—enhanced by disruptions in cell polarity—has been shown to endow breast cancer cells with cancer stem cell characteristics. The relationship between the pro-oncogene SnoN and the anti-oncogene SCRIB, as well as their connection to the Hippo pathway, is quite fascinating. Current models suggest that the interaction between SCRIB and SnoN is essential for preventing TAZ activity. When this interaction is disrupted, TAZ becomes stabilized. This study aims to gain further insight into the SCRIB-SnoN interaction by examining their binding specificities and identifying additional protein interactions that occur upstream of Hippo kinase activity, with the goal of downregulating TAZ. The SCRIB-SnoN interaction appears to be a promising target for diminishing the TAZ-dependent stemness of breast cancer cells. Understanding the biological function of this interaction is key to unraveling the relationship between SCRIB-dependent cell polarity, Hippo signaling, and the development of cancer stem cell characteristics in breast tumors. Additionally, it may provide valuable insights into mechanisms for controlling cancer cell growth.