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Targeting Akt signaling in breast cancer : expression of phosphorylated Akt in breast tumors and the efficacy of celecoxib analogues as potential inhibitors of Akt activation

University of British Columbia

Constitutive activation of Akt, due to overexpression of receptor tyrosine kinases (RTKs) or loss of phosphatase and tensin homologue (PTEN), contributes to the development of breast cancer and confers resistance to conventional therapies. Therefore, the Akt signaling pathway is an attractive target for therapeutic intervention. Utilizing tumor tissue microarrays we show that 58% (225/390) of breast cancers express moderate to high levels of activated Akt (P-Akt), compared with 35% (9/26) of normal breast tissues. Additionally we find that P-Akt expression in primary breast cancer is significantly correlated with the expression of three RTKs, human epidermal growth factor receptor-2 (HER-2), insulin like growth factor receptor-1 (IGF-1R) and ephrin receptor EphA2, as well as integrin-linked kinase (ILK) and the transcription factors growth factor independence 1 (GFI-1) and Y box-binding protein-1 (YB-1). Further, we examined the potential of three celecoxib analogues for the treatment of breast cancers expressing P-Akt. We found that all three analogues, OSU-03008, OSU-03012, and OSU-03013, were able to disrupt Akt signaling in the MDA-MB-453 breast cancer cell line, which overexpresses HER-2 and has very high P-Akt levels. Treating the cells for two hours with the compounds inhibited Akt phosphorylation and kinase activity, as well as its downstream signaling through glycogen synthase kinase- 3β (GSK3-β), at concentrations well below that of celecoxib (≤10 μM). Disruption of Akt phosphorylation by OSU-03012 and OSU-03013 was followed by an induction of apoptosis after 12 to 24 hours, whereas OSU-03008 did not cause cell death. When tested against a panel of three other breast cancer cell lines, OSU-03012 and OSU 03013 (but not OSU-03008) were found to reduce viability in cell lines which did not constitutively express P-Akt (MDA-MB-231, MCF-7). Overexpression of constitutively activated Akt in the MDA-MB-453 or MCF-7 cells was not able to rescue cells from the cytotoxicity of OSU-03012 or OSU-03013. These data suggest that the celecoxib analogues are potentially useful for inhibiting Akt signaling in breast cancer, although it appears that the cytotoxic effects of OSU-03012 and OSU-03013 occur through additional targets. These inhibitors could hopefully be used in combination with other therapies to bypass Akt-mediated drug resistance.

Thesis/Dissertation

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2009-12-03

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http://hdl.handle.net/2429/16264

Experimental Medicine

University of British Columbia

UBCV

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