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Title: EGFR and Src are involved in indole-3-carbinol-induced death and cell cycle arrest of human breast cancer cells
Authors: Moiseeva, Elena P.
Heukers, Raimond
Manson, Margaret M.
First Published: 6-Sep-2006
Publisher: Oxford University Press
Citation: Carcinogenesis, 2007, 28 (2), pp. 435-445
Abstract: Indole-3-carbinol (I3C), a dietary chemopreventive compound, induced marked reduction in epidermal growth factor receptor (EGFR) prior to cell death in cells representing three breast cancer subtypes. Signalling 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 signalling 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.
DOI Link: 10.1093/carcin/bgl171
ISSN: 0143-3334
Version: Post print
Status: Peer reviewed
Type: Article
Rights: © The Author 2006. Deposited with reference to the publisher's archiving policy available on the SHERPA/RoMEO website. This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Carcinogenesis following peer review. The definitive publisher-authenticated version Carcinogenesis, 2007, 28 (2), pp. 435-445 is available online at:
Appears in Collections:Published Articles, Dept. of Cancer Studies and Molecular Medicine

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