Early changes in [18F] FDG incorporation by breast cancer cells treated with trastuzumab in normoxic conditions

Role of the Akt-pathway, glucose transport and HIF-1α

Ian Neil Fleming, Alexandra Andriu, Timothy Andrew Davies Smith

Research output: Contribution to journalArticle

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Abstract

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.
Original languageEnglish
Pages (from-to)241-248
Number of pages8
JournalBreast Cancer Research and Treatment
Volume144
Issue number4
Early online date13 Feb 2014
DOIs
Publication statusPublished - 1 Apr 2014

Fingerprint

Fluorodeoxyglucose F18
Breast Neoplasms
Glucose
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Drug Delivery Systems
Phosphatidylinositol 3-Kinases
Cell Line
Trastuzumab
Tumor Cell Line
Therapeutics
Down-Regulation
Growth

Keywords

  • [18F]FDG
  • glucose transport
  • PI3/AKT
  • trastuzumab

Cite this

Early changes in [18F] FDG incorporation by breast cancer cells treated with trastuzumab in normoxic conditions : Role of the Akt-pathway, glucose transport and HIF-1α. / Fleming, Ian Neil; Andriu, Alexandra; Smith, Timothy Andrew Davies.

In: Breast Cancer Research and Treatment, Vol. 144, No. 4, 01.04.2014, p. 241-248.

Research output: Contribution to journalArticle

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