Role of P13 Kinase Signaling Pathways in Polarity Determination of Human Mammary Epithelial Cells Grown in Three-Dimensional Extracellular Matrix
Abstract
Loss of tissue polarity and increased proliferation are the characteristic alterations of the breast tumor phenotype. To investigate these processes, we have used a three-dimensional (3D) culture system in which malignant human breast cells can be reverted to a normal phenotype. Exposure to inhibitors of phosphatidylinositol 3-kinase (PI3K) leads to decreased proliferation and restored tissue polarity. We show that Akt and Rac1 act as downstream effectors of PI3K and function as control points of cellular proliferation and tissue polarity, respectively. Expression of active Akt causes increased proliferation without affecting basal tissue polarity, whereas active Rac1 prevents the restoration of tissue polarity but does not affect proliferation; when activated in combination, these two signaling effectors are sufficient to prevent restoration of normal phenotype. Our results also show that the entire PI3K signaling pathway is an integral component of the overall signaling network induced by growth in 3D, as reversion effected by inhibition of PI3K signaling also down-modulates the endogenous levels of upstream modulators of PI3K, beta1 integrin and EGFR, and upregulates the antagonist of PI3K, PTEN. Our results reveal key events downstream of PI3K that act synergistically to maintain tissue polarity and that when disrupted produce the malignant phenotype.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2004
- Accession Number
- ADA430632
Entities
People
- Hong Liu
Organizations
- University of California, Berkeley