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Shapiro, David J. Cunningham, Thomas D. 2015-09-25T22:28:12Z 2015-09-25T22:28:12Z 10000-01-01 2008 2008 To test the effect of estrogen receptor (ER) ligands that induce PI-9 on TRAIL-mediated cytotoxicity, we used MCF-7, human breast cancer cells. In MCF-7 cells, induction of PI-9 by 17beta-estradiol (E2) inhibited TRAIL-mediated cytotoxicity. This is the first demonstration that regulation of PI-9 expression from its endogenous promoter results in production of sufficient PI-9 to inhibit cytotoxocity by members of the TNF superfamily. To test the effect of the selective estrogen receptor modulator (SERM), 4-hydroxytamoxifen (OHT) (the active metabolite of tamoxifen), we used a tet-inducible MCF-7 cell model system, termed MCF7ERalphaHA cells. In MCF7ERalphaHA cells, OHT is a full agonist and induces higher levels of PI-9 than E2. In MCF7ERalphaHA cells, induction of high levels of PI-9 by both OHT and E2 inhibits TRAIL-mediated cytotoxicity. Our data suggest a new mechanism by which estrogen may contribute to the development of breast cancer. Furthermore, the powerful induction of PI-9 by OHT suggests a molecular mechanism to explain resistance to tamoxifen therapy in some of the often highly lethal breast cancers containing high levels of ER. Made available in DSpace on 2015-09-25T22:28:12Z (GMT). No. of bitstreams: 2 license.txt: 4848 bytes, checksum: 96035ab3f5e1c23cc7138a224ce498bd (MD5) 3337746.pdf: 1112153 bytes, checksum: 0184ee3aa66503e8d7f16b643abc1e03 (MD5) Previous issue date: 2008 Embargo set by: Seth Robbins for item 86135 Lift date: Forever Reason: Restricted to the U of I community idenfinitely during batch ingest of legacy ETDs Restricted to the U of I community idenfinitely during batch ingest of legacy ETDs U of I Only 81 p. Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2008. http://hdl.handle.net/2142/84854 (MiAaPQ)AAI3337746 eng Biology, Cell Estrogen Inducible Proteinase Inhibitor 9 Protects Target Cells From Immune Surveillance and Apoptosis text Biochemistry Biochemistry University of Illinois at Urbana-Champaign Dissertation Ph.D.