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Article

Survival Is Related to Estrogen Signal Transduction Pathway Activity in Postmenopausal Women Diagnosed with High-Grade Serous Ovarian Carcinoma

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Department of Obstetrics and Gynecology, Catharina Cancer Institute, Catharina Hospital, P.O. Box 1350, 5602 ZA Eindhoven, The Netherlands
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Department of Obstetrics and Gynecology, Radboud Institute for Health Sciences, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
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GROW School for Oncology and Developmental Biology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
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Molecular Pathway Diagnostics, Philips, High Tech Campus 11, 5656 AE Eindhoven, The Netherlands
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Laboratory for Pathology and Medical Microbiology (Stichting PAMM), P.O. Box 2, 5500 AA Veldhoven, The Netherlands
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Laboratory for Pathology, Jeroen Bosch Hospital, P.O. Box 90153, 5200 ME ‘s-Hertogenbosch, The Netherlands
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Department of Obstetrics and Gynecology, Elisabeth-TweeSteden Hospital, P.O. Box 90151, 5000 LC Tilburg, The Netherlands
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Radboud Institute for Health Sciences, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
*
Authors to whom correspondence should be addressed.
Dual first author.
Academic Editors: Andrew Stephens and Maree Bilandzic
Cancers 2021, 13(20), 5101; https://doi.org/10.3390/cancers13205101
Received: 30 August 2021 / Revised: 29 September 2021 / Accepted: 5 October 2021 / Published: 12 October 2021
(This article belongs to the Special Issue Ovarian Cancer Biomarkers, Diagnostic and Therapeutic Technologies)
All cells have a complex internal network of ‘communication chains’ called signal transduction pathways (STPs). Through interaction of different proteins in STPs, they are partly responsible for the behavior of a cell. In our study, we investigated the activity of six STPs in 85 women with advanced stage high-grade serous ovarian cancer (HGSC). To investigate the relation between and differences in survival and STP activity, women with a short disease-free survival (below 12 months) and a long disease-free survival (above 24 months) were included. We found no differences in mean STP activity between short-term survivors (52 women) and long-term survivors (33 women). However, when we analyzed postmenopausal women, we found that both disease-free and overall survival were related to estrogen receptor (ER) pathway signaling. This indicates that a better survival outcome was related to a more active ER pathway in this subgroup.
High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, has a high mortality rate. Although there are some factors associated with survival, such as stage of disease, there are remarkable differences in survival among women diagnosed with advanced stage disease. In this study, we investigate possible relations between survival and signal transduction pathway (STP) activity. We assessed the functional activity of the androgen receptor (AR), estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-β) and canonical wingless-type MMTV integration site (Wnt) pathway in 85 primary tumor samples of patients with FIGO stage IIIC to IVB HGSC and disease-free survival (DFS) below 12 (n = 52) or over 24 months (n = 33). There were no significant differences in median pathway activity between patients with a short and long DFS. In univariate Cox proportional hazards analysis, ER pathway activity was related to a favorable DFS and overall survival (OS) in postmenopausal women (p = 0.033 and p = 0.041, respectively), but not in premenopausal women. We divided the postmenopausal group into subgroups based on ER pathway activity quartiles. Survival analysis revealed that postmenopausal women in the lowest ER quartile had a shorter DFS and OS (log-rank p = 0.006 and p < 0.001, respectively). Furthermore, we were able to form subgroups of patients based on an inverse relation between ER and PI3K pathway activity. In conclusion, in postmenopausal patients with advanced stage HGSC, a poorer survival outcome was associated with low functional ER pathway activity. View Full-Text
Keywords: estrogen signaling; ovarian cancer; signal transduction pathways estrogen signaling; ovarian cancer; signal transduction pathways
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MDPI and ACS Style

van Lieshout, L.; van der Ploeg, P.; Wesseling-Rozendaal, Y.; van de Stolpe, A.; Bosch, S.; Lentjes-Beer, M.; Ottenheijm, M.; Meriaan, A.; Vos, C.; de Hullu, J.; Massuger, L.; Bekkers, R.; Piek, J. Survival Is Related to Estrogen Signal Transduction Pathway Activity in Postmenopausal Women Diagnosed with High-Grade Serous Ovarian Carcinoma. Cancers 2021, 13, 5101. https://doi.org/10.3390/cancers13205101

AMA Style

van Lieshout L, van der Ploeg P, Wesseling-Rozendaal Y, van de Stolpe A, Bosch S, Lentjes-Beer M, Ottenheijm M, Meriaan A, Vos C, de Hullu J, Massuger L, Bekkers R, Piek J. Survival Is Related to Estrogen Signal Transduction Pathway Activity in Postmenopausal Women Diagnosed with High-Grade Serous Ovarian Carcinoma. Cancers. 2021; 13(20):5101. https://doi.org/10.3390/cancers13205101

Chicago/Turabian Style

van Lieshout, Laura, Phyllis van der Ploeg, Yvonne Wesseling-Rozendaal, Anja van de Stolpe, Steven Bosch, Marjolein Lentjes-Beer, Meggy Ottenheijm, Annelen Meriaan, Caroline Vos, Joanne de Hullu, Leon Massuger, Ruud Bekkers, and Jurgen Piek. 2021. "Survival Is Related to Estrogen Signal Transduction Pathway Activity in Postmenopausal Women Diagnosed with High-Grade Serous Ovarian Carcinoma" Cancers 13, no. 20: 5101. https://doi.org/10.3390/cancers13205101

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