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Farnesoid X receptor inhibits tamoxifen-resistant MCF-7 breast cancer cell growth through downregulation of HER2 expression

Oncogene volume 30, pages 4129–4140 (2011)Cite this article

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Abstract

Tamoxifen (Tam) treatment is a first-line endocrine therapy for estrogen receptor-α-positive breast cancer patients. Unfortunately, resistance frequently occurs and is often related with overexpression of the membrane tyrosine kinase receptor HER2. This is the rationale behind combined treatments with endocrine therapy and novel inhibitors that reduce HER2 expression and signaling and thus inhibit Tam-resistant breast cancer cell growth. In this study, we show that activation of farnesoid X receptor (FXR), by the primary bile acid chenodeoxycholic acid (CDCA) or the synthetic agonist GW4064, inhibited growth of Tam-resistant breast cancer cells (termed MCF-7 TR1), which was used as an in vitro model of acquired Tam resistance. Our results demonstrate that CDCA treatment significantly reduced both anchorage-dependent and anchorage-independent epidermal growth factor (EGF)-induced growth in MCF-7 TR1 cells. Furthermore, results from western blot analysis and real-time reverse transcription–PCR revealed that CDCA treatment reduced HER2 expression and inhibited EGF-mediated HER2 and p42/44 mitogen-activated protein kinase (MAPK) phosphorylation in these Tam-resistant breast cancer cells. Transient transfection experiments, using a vector containing the human HER2 promoter region, showed that CDCA treatment downregulated basal HER2 promoter activity. This occurred through an inhibition of nuclear factor-κB transcription factor binding to its specific responsive element located in the HER2 promoter region as revealed by mutagenesis studies, electrophoretic mobility shift assay and chromatin immunoprecipitation analysis. Collectively, these data suggest that FXR ligand-dependent activity, blocking HER2/MAPK signaling, may overcome anti-estrogen resistance in human breast cancer cells and could represent a new therapeutic tool to treat breast cancer patients that develop resistance.

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Acknowledgements

This work was supported by AIRC grants, MIUR Ex 60% 2009, PRIN 2009 and Lilli Funaro Foundation. NIH/NCI R01 CA72038 and RP101251 from the Cancer Prevention and Research Institute of Texas (SAWF). We thank Dr Mien-Chie Hung for providing the pNeuLite plasmid and Dr T.A. Kocarek for providing the FXR-responsive reporter gene and FXR-DN expression plasmids. We also thank Dr Rachel Schiff for providing the MCF-7/HER2-18 cells.

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  1. C Giordano and S Catalano: These authors contributed equally to this work.

Authors and Affiliations

  1. Centro Sanitario, University of Calabria, Arcavacata di Rende, Italy

    C Giordano, S Catalano, I Barone, D Bonofiglio & S Andò

  2. Department of Pharmaco-Biology, University of Calabria, Arcavacata di Rende, Italy

    S Catalano, S Panza, D Vizza, D Bonofiglio & L Gelsomino

  3. Department of Cellular Biology, University of Calabria, Arcavacata di Rende, Italy

    I Barone, P Rizza & S Andò

  4. Lester and Sue Smith Breast Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

    S A W Fuqua

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  1. C Giordano
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Correspondence to S Andò.

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Giordano, C., Catalano, S., Panza, S. et al. Farnesoid X receptor inhibits tamoxifen-resistant MCF-7 breast cancer cell growth through downregulation of HER2 expression. Oncogene 30, 4129–4140 (2011). https://doi.org/10.1038/onc.2011.124

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