HER-2 overexpression does not guarantee response to HER2-targeting drugs such as trastuzumab, which is cardiotoxic and expensive, so early detection of response status is crucial. Factors influencing [(18)F]FDG incorporation in the timeframe of cell signalling down-regulation subsequent to trastuzumab treatment are investigated to provide a better understanding of the relationship between growth response and modulation of [(18)F]FDG incorporation. HER-2-overexpressing breast tumour cell lines, MDA-MB-453, SKBr3 and BT474 and MDA-MB-468 (HER2 non-over-expressor) were treated with trastuzumab (4 h) and probed for AKT, pAKT, ERK1/2, pERK1/2 and HIF-1α to determine early signalling pathway inhibitory effects of trastuzumab. Cells incubated with trastuzumab and/or PI3K inhibitor LY294002 and ERK1/2 inhibitor U0126 and glucose transport and [(18)F]FDG incorporation measured. Cell lines expressed AKT, pAKT, ERK1/2 and pERK1/2 but not HIF-1α. Trastuzumab treatment decreased pAkt but not pERK1/2 levels. Trastuzumab did not further inhibit AKT when maximally inhibited with LY294002. Treatment with LY294002 and trastuzumab for 4 h decreased [(18)F]FDG incorporation in BT474 and MDA-MB-453 but not SKBr3 cells. LY294002 inhibited glucose transport by each cell line, but the glucose transport rate was tenfold higher by SKBr3 cells than BT474 and MDA-MB-453 cells. AKT-induced uptake of [(18)F]FDG was found to be HIF-1α independent in breast cancer cell lines. AKT inhibition level and tumour cell glucose transport rate can influence whether or not PI3K inhibitors affect [(18)F]FDG incorporation which may account for the variation in preclinical and clinical findings associated with [(18)F]FDG-PET in response to trastuzumab and other HER-2 targeting drugs.
|Number of pages||8|
|Journal||Breast Cancer Research and Treatment|
|Early online date||13 Feb 2014|
|Publication status||Published - 1 Apr 2014|
- glucose transport
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- School of Medicine, Medical Sciences & Nutrition, Medical Education - Senior Lecturer (Scholarship)
- Institute of Medical Sciences
- Aberdeen Biomedical Imaging Centre
Person: Academic Related - Scholarship