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AKT-aro and HER2-aro, models for de novo resistance to aromatase inhibitors; molecular characterization and inhibitor response studies

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Abstract

Aromatase inhibitors (AI) are currently the first line therapy for estrogen receptor (ER)-positive postmenopausal women. De novo AI resistance is when a patient intrinsically does not respond to an AI therapy as well as other targeted endocrine therapy. To characterize this type of resistance and to examine potential therapies for treatment, we have generated two cell models for de novo resistance. These models derive from MCF-7 cells that stably overexpress aromatase and Akt (AKT-aro) or HER2 (HER2-aro). Evaluation of these cell lines revealed that the activities of aromatase and ER were inhibited by AI and ICI 187280 (ICI) treatment, respectively; however, cell growth was resistant to therapy. Proliferation in the presence of the pure anti-estrogen ICI, indicates that these cells do not require ER for cell growth and distinguishes these cells from the acquired AI resistant cells. We further determined that the HSP90 inhibitor 17-DMAG suppressed the growth of the AI-resistant cell lines studied. Our analysis revealed 17-DMAG-mediated decreased expression of growth promoting signaling proteins. It was found that de novo AI resistant AKT-aro and HER2-aro cells could not be resensitized to letrozole or ICI by treatment with 17-DMAG. In summary, we have generated two cell lines which display the characteristics of de novo AI resistance. Together, these data indicate the possibility that HSP90 inhibitors may be a viable therapy for endocrine therapy resistance although additional clinical evaluation is needed.

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Acknowledgments

This study was supported by NIH grants CA44735 and ES08258 to Shiuan Chen.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Tumor Cell Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA

    Cynthie Wong, Xin Wang & Shiuan Chen

  2. Department of Information Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA

    David Smith

  3. Department of Pathology, Wayne State University, Detroit, MI, 48201, USA

    Kaladhar Reddy

Authors
  1. Cynthie Wong
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  2. Xin Wang
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  3. David Smith
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Correspondence to Shiuan Chen.

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Wong, C., Wang, X., Smith, D. et al. AKT-aro and HER2-aro, models for de novo resistance to aromatase inhibitors; molecular characterization and inhibitor response studies. Breast Cancer Res Treat 134, 671–681 (2012). https://doi.org/10.1007/s10549-012-2105-6

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  • DOI: https://doi.org/10.1007/s10549-012-2105-6

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