Polarity and proliferation are controlled by distinct signaling pathways downstream of PI3-kinase in breast epithelial tumor cells: Functional bifurcation of PI3-kinase signaling pathway

Epithelial tumorigenesis is a combination of multiple genetic lesions leading to aberrant proliferation, failure to differentiate, and loss of tissue architecture/polarity and tissue-specific function. Although it is well established that aberrant proliferation is one of the most prominent feature of most cancers and that dysregulated cell proliferation control machineries are the major driving force of tumorigenesis, it is not clear whether deregulated proliferation is sufficient to initiate all tumorigenic phenotypes, or whether polarity defect is an independent factor that also contributes to cancer development.; The proper development and maintenance of polarity is essential for the formation of tissue-specific structures, organization integrity, and tissue functiona. Polarity defects are a hallmark of epithelial cancers and not only lead to loss of tissue organization/polarity and function, but also cause spatial disorganization of signaling pathways that control cell proliferation and indirectly affect cellular proliferation so as to increase the potential of cells to proceed to aggressive tumors.; Overexpression or aberrant activation of many kinases have been found in a variety of human cancers including breast cancers, and has been shown to transform mammalian cells and cause tumor development in mice. The multiple functions of each oncogenic kinase predicts that the ultimate formation of a tumor may not be the result of simply deregulated proliferation, the most prominent feature controlled by oncogenic kinases, but also the result of convergence of all the phenotypic defects caused by downstream effectors with distinct functions. However, it is unclear whether deregulated proliferation is the sole cause of other tumor-causing defects, such as loss of tissue achitecture and polarity. My thesis aims to investigate whether altered proliferation is sufficient to change tissue polarity or whether deregulation of polarity is an independent, separable variable contributing to breast cancer development. (Abstract shortened by UMI.)...