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Published on: December 19, 2018
Monitoring the Crosstalk Between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 with PET
I F Antunes1, G A P Hospers2, J W A Sijbesma3
1Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. i.farinha.antunes@umcg.nl.
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-17β-estradiol ([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.
Insights
Positron emission tomography (PET) imaging can detect changes in estrogen receptor (ER) expression in ovarian cancer tumors treated with HER2-targeted therapies. This noninvasive method helps understand the complex interplay between ER and HER2 signaling, crucial for overcoming treatment resistance.
Area of Science:
- Oncology
- Molecular Imaging
- Biochemistry
Background:
- Ovarian cancer (OC) presents poor survival rates due to late detection and resistance to chemotherapy.
- Estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) targeted therapies are used for OC, but resistance develops.
- HER2 overexpression can cause resistance to ER-targeted treatment, while trastuzumab may increase ER expression, enhancing sensitivity to anti-estrogen therapy.
Purpose of the Study:
- To investigate the crosstalk between ER and HER2 signaling in ovarian cancer.
- To evaluate the utility of Positron Emission Tomography (PET) for detecting in vivo changes in ER expression induced by HER2-targeted treatment.
Main Methods:
- Athymic nude mice bearing SKOV3 human ovarian cancer cells (HER2+/ER+) were treated with vehicle, trastuzumab, or lapatinib for two weeks.
- Estrogen receptor (ER) expression was assessed noninvasively using PET imaging with 16α-[18F]-fluoro-17β-estradiol ([18F]FES).
- Tumor ER and HER2 levels were further quantified ex vivo using Western blotting and immunohistochemistry.
Main Results:
- All treatments resulted in smaller tumors compared to the vehicle control group.
- PET imaging revealed significantly higher [18F]FES uptake (indicating increased ER expression) in tumors treated with trastuzumab (+29%) and lapatinib (+20%) compared to controls.
- Ex vivo analyses confirmed the PET findings, demonstrating agreement between imaging and molecular measurements.
Conclusions:
- 18F-Fluoroestradiol (FES)-PET imaging is a valuable noninvasive tool for monitoring ER expression changes in response to HER2-targeted therapies in ovarian cancer.
- This imaging approach can elucidate the intricate crosstalk between ER and HER2 signaling pathways.
- Understanding this crosstalk is essential for developing strategies to overcome acquired resistance in ovarian cancer treatment.
