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Title:Estrogen Receptor -Dependent and Estrogen Receptor-Independent Pathways for Tamoxifen and 4-Hydroxytamoxifen-Induced Programmed Cell Death
Author(s):Obrero, Maria Constancia Tabermejo
Doctoral Committee Chair(s):Shapiro, David J.
Department / Program:Biochemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Biology, Cell
Abstract:One of the most common methods of breast cancer treatment is antiestrogen treatment. The therapeutic efficacy of the selective estrogen receptor modulator tamoxifen (TAM) in cancer therapy is thought to arise from its ability to compete with estrogens for binding to the ER. We show that TAM and its active metabolite, 4-hydroxytamoxifen (OHT), induce programmed cell death through distinct ER-dependent and ER-independent pathways. The ER-independent pathway requires 10--20 muM TAM or OHT and occurs in ER-negative cells. Nanomolar concentrations of OHT activate an ER-dependent pathway. 17beta-estradiol, raloxifene, and ICI 182,780 are all effective competitors, which block OHT-ER and Tam-ER-dependent cell death. Since the p38-specific inhibitor SB203580 blocks OHT-ER induced cell death, stress kinase pathways are likely involved. ER-independent cell death triggers classic caspase-dependent apoptosis. However, while OHT-ER triggers some hallmarks of apoptosis, including Bax translocation and cytochrome c release, the absence of PARP cleavage or DNA laddering indicate caspase-independent programmed cell death. The divergence from classical apoptosis appears to be at the level of procaspase 9 activation. This study describes a unique ER-dependent, programmed cell death-promoting activity of TAM and OHT that is distinct from their ability to compete with estrogens for binding to the ER.
Issue Date:2002
Description:130 p.
Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2002.
Other Identifier(s):(MiAaPQ)AAI3070400
Date Available in IDEALS:2015-09-25
Date Deposited:2002

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