Estrogen Inducible Proteinase Inhibitor 9 Protects Target Cells From Immune Surveillance and Apoptosis

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biochemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Cunningham, Thomas D.

Contributors dc:contributor

• Shapiro, David J.

• Biology, Cell

Language dc:language

eng

Identifier

(MiAaPQ)AAI3337746

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/84854