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The importance of HER2 signaling in the tumor-initiating cell population in aromatase inhibitor-resistant breast cancer

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Abstract

Aromatase inhibitors (AIs) are an effective therapy in treating estrogen receptor-positive breast cancer. Nonetheless, a significant percentage of patients either do not respond or become resistant to AIs. Decreased dependence on ER-signaling and increased dependence on growth factor receptor signaling pathways, particularly human epidermal growth factor receptor 2 (EGFR2/HER2), have been implicated in AI resistance. However, the role of growth factor signaling remains unclear. This current study investigates the possibility that signaling either through HER2 alone or through interplay between epidermal growth factor receptor 1 (EGFR/HER1) and HER2 mediates AI resistance by increasing the tumor initiating cell (TIC) subpopulation in AI-resistant cells via regulation of stem cell markers, such as breast cancer resistance protein (BCRP). TICs and BCRP are both known to be involved in drug resistance. Results from in vitro analyses of AI-resistant versus AI-sensitive cells and HER2-versus HER2+ cells, as well as from in vivo xenograft tumors, indicate that (1) AI-resistant cells overexpress both HER2 and BCRP and exhibit increased TIC characteristics compared to AI-sensitive cells; (2) inhibition of HER2 and/or BCRP decrease TIC characteristics in letrozole-resistant cells; and (3) HER2 and its dimerization partner EGFR/HER1 are involved in the regulation of BCRP. Overall, these results suggest that reducing or eliminating the TIC subpopulation with agents that target BCRP, HER2, EGFR/HER1, and/or their downstream kinase pathways could be effective in preventing and/or treating acquired AI resistance.

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Acknowledgments

This research was supported in part by RO1 CA 62483 and a Komen Scholars award to Angela Brodie. The authors would like to thank Dr Ferenc Livak for his help with flow cytometry.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology and Experiment Therapeutics, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Rabia A. Gilani, Armina A. Kazi, Preeti Shah, Amanda J. Schech, Gauri Sabnis, Anil K. Jaiswal & Angela H. Brodie

  2. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Saranya Chumsri

  3. University of Maryland Marelene and Steward Greenebaum Cancer Center, University of Maryland, Baltimore, MD, 21201, USA

    Saranya Chumsri, Gauri Sabnis, Anil K. Jaiswal & Angela H. Brodie

  4. Department of Biology, Loyola University Maryland, Baltimore, MD, 21210, USA

    Armina A. Kazi

  5. Department of Pharmacology and Experiment Therapeutics, University of Maryland School of Medicine, Health Science Facilities, Room 580G, 685 West Baltimore Street, Baltimore, MD, 21201, USA

    Angela H. Brodie

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  1. Rabia A. Gilani
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  2. Armina A. Kazi
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  3. Preeti Shah
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  4. Amanda J. Schech
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  5. Saranya Chumsri
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  6. Gauri Sabnis
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  7. Anil K. Jaiswal
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  8. Angela H. Brodie
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Corresponding author

Correspondence to Angela H. Brodie.

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Rabia A. Gilani and Armina A. Kazi contributed equally to this study.

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Gilani, R.A., Kazi, A.A., Shah, P. et al. The importance of HER2 signaling in the tumor-initiating cell population in aromatase inhibitor-resistant breast cancer. Breast Cancer Res Treat 135, 681–692 (2012). https://doi.org/10.1007/s10549-012-2148-8

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