Monitoring the Crosstalk Between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 with PET

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 10 6 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-[ 18 F]-fluoro-17βestradiol ([ 18 F]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 [ 18 F]FES maximum standardize tumor uptake (SUV max) 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.

Estrone-Conjugated PEGylated Liposome Co-Loaded Paclitaxel and Carboplatin Improve Anti-Tumor Efficacy in Ovarian Cancer and Reduce Acute Toxicity of Chemo-Drugs

“…The cytotoxicity potential of blank liposome, free drugs and drug-loaded liposomes against SKOV-3 (ER-positive) cells 72 was assessed by CCK-8 assay. As expected, over 90% of the cells survived with blank liposome during the incubation period, indicating that the blank liposomes had no cytotoxicity against SKOV-3 cells ( Figure S1 ).…”

Effects of clinical treatment decisions on long-term survival outcomes of locally advanced breast cancer with different molecular subtypes based on the SEER database

“…However, we found that the treatment of TPBC is far more complex than we imagined, and it is not a simple 1 + 1 = 2 mode. Since TPBC has both estrogen receptor and HER2 signaling pathways, some studies have shown that the coexistence of these two pathways will cause bidirectional interference of treatment [22,33,34],which can induce the development of resistance to endocrine therapy and anti-HER2 therapy [35].Relevant literature indicates that the addition of trastuzumab in the treatment of some TPBCs does not lead to better survival outcomes [36],and the biological behavior of these patients is more inclined to the Luminal type, and the degree of response to trastuzumab is lower [26].…”