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Cellular Oncology

, Volume 38, Issue 2, pp 155–164 | Cite as

Synergy of leptin/STAT3 with HER2 receptor induces tamoxifen resistance in breast cancer cells through regulation of apoptosis-related genes

  • Vassilis Papanikolaou
  • Nikolaos Stefanou
  • Stephanie Dubos
  • Ioanna Papathanasiou
  • Maria Palianopoulou
  • Vaia Valiakou
  • Aspasia Tsezou
Original Paper

Abstract

Purpose

Tamoxifen is a major treatment modality for estrogen receptor positive breast cancer, but the occurrence of resistance remains a problem. Recently, obesity-related leptin has been found to interfere with tamoxifen in breast cancer MCF-7 cells. In the present study we investigated the effect of leptin on three tamoxifen-treated breast cancer cell types (i.e., MDA-MB-231, MCF-7 and MCF-7/HER2).

Methods

The effect of tamoxifen/leptin treatment was evaluated using a MTT cell viability assay. mRNA expression was assessed by real time PCR and protein expression by Western blotting. WWOX, Survivin and BCL2 gene promoter activities were evaluated by chromatin immunoprecipitation.

Results

Cell viability assays revealed that estrogen receptor negative MDA-MB-231 cells were resistant, that estrogen receptor positive MCF-7 cells were sensitive and that MCF-7/HER2 cells were relatively resistant to tamoxifen, while leptin co-administration ‘rescued’ MCF-7 and, especially, MCF-7/HER2 cells from the anti-proliferative effect of tamoxifen. The cell lines also exhibited a different phosphorylation status of STAT3, a transcription factor that is activated by the obesity related leptin receptor b (Ob-Rb). Most importantly, chromatin immunoprecipitation assays revealed differential STAT3 binding to the anti-apoptotic BCL2 and pro-apoptotic WWOX gene promoters in MCF-7 and MCF-7/HER2 cells, leading to concomitant modifications of its mRNA/protein expression levels, thus providing a selective advantage to HER2 over-expressing MCF-7/HER2 cells after treatment with tamoxifen and tamoxifen plus leptin.

Conclusions

Our study provides novel evidence indicating that synergy between the leptin/Ob-Rb/STAT3 signalling pathway and the HER2 receptor protects tamoxifen-treated HER2 over-expressing cells from the inhibitory effect of tamoxifen through differential regulation of apoptosis-related genes.

Keywords

Tamoxifen Leptin HER2 receptor STAT3 Breast cancer BCL2 WWOX 

Notes

Conflict of interest

The authors have no conflict of interest to report with respect to this work.

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Copyright information

© International Society for Cellular Oncology 2014

Authors and Affiliations

  • Vassilis Papanikolaou
    • 1
  • Nikolaos Stefanou
    • 1
  • Stephanie Dubos
    • 1
  • Ioanna Papathanasiou
    • 2
  • Maria Palianopoulou
    • 2
  • Vaia Valiakou
    • 1
  • Aspasia Tsezou
    • 1
    • 2
    • 3
  1. 1.Department of Biomedical Research and Technology, Institute for Research and Technology-Thessaly (I.RE.TE.TH)Centre for Research and Technology-Hellas (CE.R.T.H.)LarissaGreece
  2. 2.Department of Cytogenetics and Molecular GeneticsUniversity of Thessaly, Faculty of MedicineLarissaGreece
  3. 3.Department of BiologyUniversity of Thessaly, Faculty of MedicineLarissaGreece

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