University of Illinois Urbana-Champaign

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

Cunningham, Thomas D.

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Description

Title
Estrogen Inducible Proteinase Inhibitor 9 Protects Target Cells From Immune Surveillance and Apoptosis
Author(s)
Cunningham, Thomas D.
Issue Date
2008
Doctoral Committee Chair(s)
Shapiro, David J.
Department of Study
Biochemistry
Discipline
Biochemistry
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Cell
Language
eng
Abstract
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.
Graduation Semester
2008
Type of Resource
text
Permalink
http://hdl.handle.net/2142/84854

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