Breast Cancer Research and Treatment

, Volume 146, Issue 2, pp 273–285

Tamoxifen through GPER upregulates aromatase expression: a novel mechanism sustaining tamoxifen-resistant breast cancer cell growth

  • Stefania Catalano
  • Cinzia Giordano
  • Salvatore Panza
  • Francesca Chemi
  • Daniela Bonofiglio
  • Marilena Lanzino
  • Pietro Rizza
  • Francesco Romeo
  • Suzanne A. W. Fuqua
  • Marcello Maggiolini
  • Sebastiano Andò
  • Ines Barone
Preclinical study

DOI: 10.1007/s10549-014-3017-4

Cite this article as:
Catalano, S., Giordano, C., Panza, S. et al. Breast Cancer Res Treat (2014) 146: 273. doi:10.1007/s10549-014-3017-4

Abstract

Tamoxifen resistance is a major clinical challenge in breast cancer treatment. Aromatase inhibitors are effective in women who progressed or recurred on tamoxifen, suggesting a role of local estrogen production by aromatase in driving tamoxifen-resistant phenotype. However, the link between aromatase activity and tamoxifen resistance has not yet been reported. We investigated whether long-term tamoxifen exposure may affect aromatase activity and/or expression, which may then sustain tamoxifen-resistant breast cancer cell growth. We employed MCF-7 breast cancer cells, tamoxifen-resistant MCF-7 cells (MCF-7 TR1 and TR2), SKBR-3 breast cancer cells, cancer-associated fibroblasts (CAFs1 and CAFs2). We used tritiated-water release assay, realtime-RT-PCR, and immunoblotting analysis for evaluating aromatase activity and expression; anchorage-independent assays for growth; reporter-gene, electrophoretic-mobility-shift, and chromatin-immunoprecipitation assays for promoter activity studies. We demonstrated an increased aromatase activity and expression, which supports proliferation in tamoxifen-resistant breast cancer cells. This is mediated by the G-protein-coupled receptor GPR30/GPER, since knocking-down GPER expression or treatment with a GPER antagonist reversed the enhanced aromatase levels induced by long-term tamoxifen exposure. The molecular mechanism was investigated in ER-negative, GPER/aromatase-positive SKBR3 cells, in which tamoxifen acts as a GPER agonist. Tamoxifen treatment increased aromatase promoter activity through an enhanced recruitment of c-fos/c-jun complex to AP-1 responsive elements located within the promoter region. As tamoxifen via GPER induced aromatase expression also in CAFs, this pathway may be involved in promoting aggressive behavior of breast tumors in response to tamoxifen treatment. Blocking estrogen production and/or GPER signaling activation may represent a valid option to overcome tamoxifen-resistance in breast cancers.

Keywords

Aromatase GPER Tamoxifen resistance Breast cancer 

Supplementary material

10549_2014_3017_MOESM1_ESM.ppt (154 kb)
Supplementary material 1 (PPT 151 kb)
10549_2014_3017_MOESM2_ESM.ppt (216 kb)
Supplementary material 2 (PPT 216 kb)

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Stefania Catalano
    • 1
  • Cinzia Giordano
    • 2
  • Salvatore Panza
    • 1
  • Francesca Chemi
    • 1
  • Daniela Bonofiglio
    • 1
  • Marilena Lanzino
    • 1
  • Pietro Rizza
    • 1
  • Francesco Romeo
    • 3
  • Suzanne A. W. Fuqua
    • 4
  • Marcello Maggiolini
    • 1
  • Sebastiano Andò
    • 1
  • Ines Barone
    • 1
  1. 1.Department of Pharmacy, Health and Nutritional SciencesUniversity of CalabriaArcavacata di RendeItaly
  2. 2.Centro SanitarioUniversity of CalabriaArcavacata di RendeItaly
  3. 3.Division of Anatomo-PathologyAnnunziata HospitalCosenzaItaly
  4. 4.Breast CenterBaylor College of MedicineHoustonUSA

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