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Role of PI3 Kinase Signaling Pathways in Polarity Development of Human Mammary Epithelial Cells Grown in Three-Dimensional Extracellular Matrix

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Annual summary 1 Sep 2005-31 Aug 2006

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Establishment and maintenance of tissue polarity is a functional property of epithelial cells and loss of this property is a hallmark of the breast cancer phenotype. We have used a 3-dimensional culture assay in which malignant human breast cells can be phenotypically reverted to a non- malignant phenotype when P13 kinase Pl3K activity is inhibited. We show here that Akt and Raci act as downstream effectors of Pl3K and function as control points of cellular proliferation and tissue polarity respectively. Signaling through these two effectors is sufficient to prevent restoration of a normal phenotype. We reveal key events downstream of Pl3K that act synergistically to maintain tissue polarity and when disrupted result in malignant phenotype. We also find that activation of Akti can prevent invasive behavior in vitro. Activated Aktl in human breast cancer cells affects cell motility and invasiveness by targeting the tumor suppressor tuberous sclerosis complex 2 TSC2 for degradation leading to reduced Rho-GTPase activity. TSC2 thus acts as a downstream target of Aktl to regulate breast cancer cell motility and invasion suggesting the need for caution in designing therapies targeting the fundtion of individual genes in epithelial tissues.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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