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Cancer Biomarkers and Prevention Group, Biocentre, University of Leicester, Leicester LE1 7RH [L. M. H., B. G-H., M. M. M., E. A. H.], and Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN [C. E. H.], United Kingdom

We have identified a new target for the chemopreventive dietary agent indole-3-carbinol (I3C) in the antiapoptotic signaling pathway involving phosphatidylinositol 3'-kinase and protein kinase B (PKB)/Akt. I3C inhibited phosphorylation and activation of PKB in the tumor-derived breast cell line MDA MB468, but not in the immortalized breast line HBL100. We propose that this cell type-specific response to I3C contributes to the differential induction of apoptosis and sensitivity to growth inhibition of the two cell lines (approximate IC₅₀ = 30 µM for the MDA MB468 line, compared with 120 µM for the HBL100 line). I3C only induced apoptosis in the MDA MB468 cell line, but at higher doses, it increased necrosis in the HBL100 line. The tumor cell line was also markedly less able to recover when I3C was removed from the culture medium. Downstream of PKB, I3C decreased nuclear factor B DNA binding, independently of an effect on IB kinase, in the MDA MB468 cell line only. The tumor suppressor PTEN, which prevents phosphorylation and activation of PKB, was expressed in HBL100 cells but was not detected in MDA MB468 cells. In corroboration of the results obtained with the breast cell lines, I3C decreased phospho-PKB levels and induced apoptosis in the prostate cell line LNCaP, which expresses very low levels of PTEN, but did not do so in PTEN-positive DU145 cells. I3C did not affect PTEN levels in any cell line. This is the first study to report a differential mechanistic response of tumor-derived and nontumorigenic cell lines and of PTEN high- and low-expressing cells to I3C and indicates a promising chemopreventive role for I3C against estrogen receptor--negative, aggressive-phenotype breast tumors.

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