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Published online 9 February 2004. doi:10.1083/jcb.200306090
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 4, 603-612
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Article

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



Hong Liu, Derek C. Radisky, Fei Wang, and Mina J. Bissell

Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720

Address correspondence to Mina J. Bissell, Life Science Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Rd., Berkeley, CA 94720. Tel.: (510) 486-4368. Fax: (510) 486-5586. email: mjbissell{at}lbl.gov

Loss of tissue polarity and increased proliferation are the characteristic alterations of the breast tumor phenotype. To investigate these processes, we used a three-dimensional (3D) culture system in which malignant human breast cells can be reverted to a normal phenotype by exposure to inhibitors of phosphatidylinositol 3-kinase (PI3K). Using this assay, we find that Akt and Rac1 act as downstream effectors of PI3K and function as control points of cellular proliferation and tissue polarity, respectively. Our results also demonstrate that the PI3K signaling pathway is an integral component of the overall signaling network induced by growth in 3D, as reversion affected by inhibition of PI3K signaling also down-modulates the endogenous levels of ß1 integrin and epidermal growth factor receptor, the upstream modulators of PI3K, and up-regulates PTEN, the antagonist of PI3K. These findings reveal key events of the PI3K pathway that play distinct roles to maintain tissue polarity and that when disrupted are instrumental in the malignant phenotype.

Key Words: three-dimensional cultures; Akt; Rac1; tumor reversion; tissue polarity

The online version of this article contains supplemental material.

F. Wang's present address is Department of Cellular and Molecular Pharmacology and the Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143.

Abbreviations used in this paper: 2D, two dimensional; 3D, three dimensional; EGFR, epidermal growth factor receptor; GSK 3ß, glycogen synthase kinase-3ß; lrBM, laminin-rich basement membrane; Myr-Akt, myristoylated Akt (constitutively active Akt); PI3K, phosphatidylinositol 3-kinase; PIP3, phosphatidylinositol 3,4,5-trisphosphate.


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