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Abstract
Most endometrial cancers express the hormone receptor estrogen receptor alpha (ER) and are driven by excess estrogen signaling. However, evaluation of the estrogen response in endometrial cancer cells has been limited by the availability of hormonally responsive in vitro models, with one cell line, Ishikawa, being used in most studies. Here, we describe a novel, adherent endometrioid endometrial cancer (EEC) cell line model, HCI-EC-23. We show that HCI-EC-23 retains ER expression and that ER functionally responds to estrogen induction over a range of passages. We also demonstrate that this cell line retains paradoxical activation of ER by tamoxifen, which is also observed in Ishikawa and is consistent with clinical data. The mutational landscape shows that HCI-EC-23 is mutated at many of the commonly altered genes in EEC, has relatively few copy-number alterations, and is microsatellite instable high (MSI-high). In vitro proliferation of HCI-EC-23 is strongly reduced upon combination estrogen and progesterone treatment. HCI-EC-23 exhibits strong estrogen dependence for tumor growth in vivo and tumor size is reduced by combination estrogen and progesterone treatment. Molecular characterization of estrogen induction in HCI-EC-23 revealed hundreds of estrogen-responsive genes that significantly overlapped with those regulated in Ishikawa. Analysis of ER genome binding identified similar patterns in HCI-EC-23 and Ishikawa, although ER exhibited more bound sites in Ishikawa. This study demonstrates that HCI-EC-23 is an estrogen- and progesterone-responsive cell line model that can be used to study the hormonal aspects of endometrial cancer.
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1 University of Utah, Department of Oncological Sciences, Huntsman Cancer Institute, Salt Lake City, USA (GRID:grid.223827.e) (ISNI:0000 0001 2193 0096)
2 University of Utah, Preclinical Research Resource, Huntsman Cancer Institute, Salt Lake City, USA (GRID:grid.223827.e) (ISNI:0000 0001 2193 0096)
3 University of Kansas Medical Center, Department of Biochemistry and Molecular Biology, Kansas City, USA (GRID:grid.412016.0) (ISNI:0000 0001 2177 6375)
4 University of New Mexico Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Division of Molecular Medicine, Departments of Internal Medicine and Obstetrics and Gynecology, Albuquerque, USA (GRID:grid.266832.b) (ISNI:0000 0001 2188 8502)
5 University of Iowa, Department of Biochemistry and Molecular Biology, Holden Comprehensive Cancer Center, Carver College of Medicine, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294)
6 University of Iowa, Department of Obstetrics and Gynecology, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294)