Reversal of Breast Cancer Phenotype to Normal in Vitro by Transposon-Mediated Mutagenesis and Identification of Associated Genetic Changes
Abstract
The highly organized architecture of cells in normal epithelial organs such as the mammary glands is lost in cancer cells. Both the normal as well as the neoplastic phenotypes can be recapitulated in 3- dimensional cell cultures in vitro. Our goal was to revert transformed breast cancer cell lines in vitro back to normal and identify the molecular and genetic changes required for this reversal. We have identified the Rho family GTPase Cdc42 and two proteins that regulate the Rho family of proteins as key molecules in this process. Inhibition of Cdc42 blocks the hyper-proliferation of transformed acini while activation causes partial reversal of polar architecture without blocking hyperproliferation suggesting that a tight control of Cdc42 function is required for maintaining normal acini. Knocking down of the Cdc42 activator p-Pix also led to a loss of polarity. A knock-down of PI 90RhoGAP which inhibits Rho was also found to cause polarity loss. Both of the loss of polarity phenotypes could be rescued by growing these acini in natural basement membrane Matrigel. These findings are consistent with the idea that epithelial transformation requires a combination of genetic as well as extracellular changes.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2007
- Accession Number
- ADA475558
Entities
People
- Anirban Datta
Organizations
- University of California, San Francisco