Monitoring the Crosstalk Between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 with PET
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RESEARCH ARTICLE
Monitoring the Crosstalk Between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 with PET I. F. Antunes,1 G. A. P. Hospers,2 J. W. A. Sijbesma,1 A. S. Boerema,1 A. van Waarde,1 A. W. J. M Glaudemans,1 R. A. J. O. Dierckx,1 E. G. E. de Vries,2 E. F. J. de Vries1 1
Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands 2 Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
Abstract Purpose: Ovarian cancer (OC) leads to poor survival rates mainly due to late stage detection and innate or acquired resistance to chemotherapy. Thus, efforts have been made to exploit the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) to treat OC. However, patients eventually become resistant to these treatments as well. HER2 overexpression contributes to the acquired resistance to ER-targeted treatment. Trastuzumab treatment, on the other hand, can result in increased expression of ER, which, in turn, increases the sensitivity of the tumors towards anti-estrogen therapy. More insight into the crosstalk between ER and HER2 signaling could improve our knowledge about acquired resistance in ovarian cancer. The aim of this study was to evaluate whether PET could be used to detect changes in ER expression induced by HER2-targeted treatment in vivo. Procedures: Male athymic nude mice were subcutaneously (sc) inoculated with 106 SKOV3 human ovarian cancer cells (HER2+/ER+). Two weeks after inoculation, tumor-bearing mice were treated intraperitoneally with either vehicle, the HER2 antibody trastuzumab (20 mg/kg, 2×/ week), or the HER2-tyrosine kinase inhibitor lapatinib (40 mg/kg, 5 days/week) for 2 weeks. Thereafter, ER expression in the tumor was assessed by PET imaging with 16α-[18F]-fluoro-17βestradiol ([18F]FES). Tumors were excised for ex vivo ER and HER2 measurement with Western blotting and immunohistochemistry. Results: All treatments led to smaller tumors than vehicle-treated tumors. Higher [18F]FES maximum standardize tumor uptake (SUVmax) was observed in animals treated with trastuzumab (+ 29 %, P = 0.002) or lapatinib (+ 20 %, P = 0.096) than in vehicle-treated controls. PET results were in agreement with ex vivo analyses. Conclusion: FES-PET imaging can detect changes in ER expression induced by HER2-targeted treatment and therefore can be used to investigate the crosstalk between ER and HER2 in a noninvasive manner. Key words: Positron emission tomography, Estrogen receptor, Human epidermal growth factor receptor, Crosstalk, [18F]FES, Imaging
Correspondence to: I. Antunes; e-mail: [email protected]
Antunes I.F. et al.: Monitoring ER-HER2 crosstalk with PET
Introduction
Materials and Methods
Ovarian cancer is often detected at a late stage, leading to poor survival rates. Despite a favorable initial response to chemotherapy, epithelial ovarian cancer (EO
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