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  • Poster Presentation
  • Open Access

The interaction of the ER with ERBB2 and PI3K results in elevated levels of AKT and p90RSK in tamoxifen-resistant MCF-7 cells

  • 1,
  • 2,
  • 3,
  • 1 and
  • 1
Breast Cancer Research20057 (Suppl 2) :P2.08

https://doi.org/10.1186/bcr1119

  • Published:

Keywords

  • Tamoxifen
  • TamR Cell
  • siRNA Technology
  • Functional Estrogen Receptor
  • Total ERBB3

Despite advances in endocrine therapies, the majority of patients receiving tamoxifen will eventually relapse while retaining functional estrogen receptors. We have previously shown, using an MCF-7 cell line (TamR) resistant to the anti-proliferative effects of tamoxifen, that elevated levels of phosphorylated AKT and p90RSK lead to an apparent ligand-independent phosphorylation of ERα ser167. Analysis of the growth factor receptors in these cells indicated elevated levels of both phosphorylated ERBB2 and total ERBB3, which we postulated formed heterodimers and activated the PI3 kinase pathway leading to elevated AKT. However, our recent data suggest that elevated AKT results from an interaction between ERα and ERBB2. This association is knocked out by treatment with the pure anti-estrogen ICI 182,780 and is absent in the WT parental cell line. Similarly, we have demonstrated an association between the p85 subunit of PI3K and ERα in TamR but not in WT cells. Treatment of the cell lines with the specific AKT inhibitor SH6 and the MEK1/2 inhibitor U0126 caused greater decrease in cell proliferation and concomitant ERα-directed transactivation in the TamR cells versus the WT, confirming that these pathways are integral to the TamR phenotype. To establish whether p90RSK or AKT was responsible for the phosphorylation of the estrogen receptor at ser167, TamR and WT cells were treated with SH6, U0126 or a combination of the two. Blocking either pathway individually had little effect on ERα ser167phosphorylation. However, a combination of the two inhibitors resulted in almost complete loss of phosphorylation. These data were confirmed using siRNA technology to suppress MAPK and AKT expression. Taken together these data suggest that, in this setting, the ER functions via a non-genomic mechanism, associating with ERBB2 and PI3K at the cell membrane leading to activation of both p90RSK and AKT. This in turn leads to phosphorylation of ERα ser167, ultimately regulating cell growth via genomic mechanisms. Although several of these complexes have previously been postulated, to our knowledge this is the first demonstration of this phenomenon in a tamoxifen-resistant cell line.

Authors’ Affiliations

(1)
Academic Department of Biochemistry and The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, London, UK
(2)
Danish Institute of Cancer Research, Copenhagen, Denmark
(3)
The Breast Unit, Royal Marsden Hospital, London, UK

Copyright

© BioMed Central 2005

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