A Model of Differential Mammary Growth Initiation by Stat3 and Asymmetric Integrin-α6 Inheritance

Abstract

Summary: Multiple cancer-related genes both promote and paradoxically suppress growth initiation, depending on the cell context. We discover an explanation for how this occurs for one such protein, Stat3, based on asymmetric cell division. Here, we show that Stat3, by Stathmin/PLK-1, regulates mitotic spindle orientation, and we use it to create and test a model for differential growth initiation. We demonstrate that Integrin-α6 is polarized and required for mammary growth initiation. Spindles orient relative to polar Integrin-α6, dividing perpendicularly in normal cells and parallel in tumor-derived cells, resulting in asymmetric or symmetric Integrin-α6 inheritance, respectively. Stat3 inhibition randomizes spindle orientation, which promotes normal growth initiation while reducing tumor-derived growth initiation. Lipid raft disruption depolarizes Integrin-α6, inducing spindle-orientation-independent Integrin-α6 inheritance. Stat3 inhibition no longer affects the growth of these cells, suggesting Stat3 acts through the regulation of spindle orientation to control growth initiation. : Stat3 acts as both a tumor suppressor and an oncogene. Morris et al. demonstrate that Stat3 can fulfill both these functions through a common mechanism: regulating mitotic spindle orientation to determine whether the growth initiation factor Integrin-α6 is inherited asymmetrically or symmetrically. Keywords: Integrin-α6, Stat3, asymmetric cell division, mammary growth initiation, mitotic spindle orientation