Abstract #2338: 17-\#946; Estradiol impairs the growth of selective estrogen receptor modulator (SERM)-resistant endometrial tumors

Previous studies in SERM resistant breast cancer models have suggested that an estrogen induced tumor regression and estrogen induced apoptosis of anti-hormonal resistance are potentially universal principles of drug resistance in estrogen target tissues. We hypothesize that estrogen induced tumor regression is a universal principle of SERM anti-hormonal resistance and therefore, estrogen treatments will significantly impede the growth of SERM resistant endometrial tumors. To test our hypothesis, we developed raloxifene resistant cell lines in vitro and tumor models in vivo . First, we developed a SERM resistant endometrial cell line, ECC1-RAL. The ECC1-RAL cells were developed by continuously passaging the endometrial ECC1 cells in media containing 1 \#956;M raloxifene (RAL) for at least one year. The ECC1-RAL cell growth is stimulated by both E 2 and RAL treatments as determined by growth assays. The ECC1-RAL cells express ER\#945; which appears to be similarly regulated as in the parental ECC1 cells and based on transcriptional assays, ER\#945; remains functional. Moreover, the basal levels of the estrogen regulated gene tff1 was up regulated 3-fold, ebag-9 4.1-fold and c-myc 3-fold, indicating significant ligand independent activities of ER\#945; in the ECC1-RAL cells The in vivo ECC1-RAL tumor xenograft model was established by injecting 10 million ECC1-RAL cells into the mammary fat pads of ovariectomized athymic nude female mice that were treated with 1.5 mg daily RAL, orally administered. The ECC1-RAL tumors were then continuously passaged in naive animals for at least 5 years. The growth of the RAL stimulated and spontaneously growing ECC1-RAL tumors was retarded by E 2 treatments. In addition, E 2 treatments impaired the growth of established ECC1-RAL tumors. Long term E 2 treatments of the estrogen treated ECC1-RAL tumors resulted in reversal of tumor phenotype from RAL stimulated and E 2 sensitive into RAL sensitive and E 2 stimulated. Continuous RAL treatments of the newly RAL sensitive tumors resulted in reversion to the original ECC1-RAL tumor phenotype, RAL stimulated and E 2 sensitive. Importantly, the initial E 2 treatments reduced the growth of the spontaneously growing ECC1-RAL tumors in the placebo groups of all subsequent experiments. Our data demonstrate that the estrogen induced tumor regression of SERM anti- hormonal resistance in estrogen target tissues previously observed in breast cancer also applies to endometrial tissues and that it is indeed a universal principle. The ability of E 2 to retard the growth of raloxifene resistant endometrial tumors and its immediate and considerable impact on the tumors in the no estrogen state provide significant clues for clinical treatment of SERM resistant endometrial tumors. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2338.