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Carcinogenesis Advance Access published online on September 6, 2006
Carcinogenesis, doi:10.1093/carcin/bgl171
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received April 28, 2006
Revised July 31, 2006
Accepted September 1, 2006

CANCER PREVENTION

EGFR and Src are involved in indole-3-carbinol-induced death and cell cycle arrest of human breast cancer cells

Elena P. Moiseeva 1 *, Raimond Heukers 1, and Margaret M. Manson 1

1 Cancer Biomarkers and Prevention Group, Departments of Biochemistry and Cancer Studies, University of Leicester, Leicester LE1 7RH, UK

* To whom correspondence should be addressed.
Elena P. Moiseeva, E-mail: em9{at}le.ac.uk


  Abstract

Indole-3-carbinol (I3C), a dietary chemopreventive compound, induced marked reduction in EGFR prior to cell death in cells representing three breast cancer subtypes. Signaling pathways, linking these events were investigated in detail. I3C modulated tyrosine phosphorylation from 30 min in four cell lines. In MDA-MB-468 and HBL100 cells, it induced Src activation after 5 h. In MDA-MB-468 cells, I3C-induced signaling between 4.5 and 7 h, which involved sequential activation of Src, EGFR, STAT-1 and STAT-3, followed by EGFR degradation. It also induced physical association between activated Src and EGFR. In MCF7 and MDA-MB-231 cells, I3C modulated expression of cell cycle-related proteins, p21Cip1, p27Kip1, cyclin E, cyclin D1 and CDK6, with upregulation of p21Cip1 and cyclin E being dependent on Src. Inhibition of EGFR by specific inhibitors PD153035 or ZD1839 increased susceptibility to I3C-induced apoptosis of MCF7, MDA-MB-468 and MDA-MB-231 cells. Inhibition of Src sensitized MDA-MB-468 and MDA-MB-231 cells to I3C, whereas overexpression of c-Src increased resistance to I3C in MDA-MB-468 and HBL100 cells. Modulation of Src in MDA-MB-468 cells influenced the basal level of EGFR expression and cell viability; the latter being positively correlated with EGFR activation levels. Therefore, EGFR and Src activities are essential for I3C-induced cell cycle arrest and death; however, I3C-induced pathways depend on specific features of breast cancer cells. The cancer types, which rely on "EGFR addiction" or Src deregulation, are likely to be susceptible to I3C.

Keywords: indole-3-carbinol; Src; EGFR; breast cancer; ZD1839; STATs.
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