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Ariazi EA , Cunliffe HE , Lewis-Wambi JS , Slifker MJ , Willis AL , Ramos P , Tapia C , Kim HR , Yerrum S , Sharma CG , Nicolas E , Balagurunathan Y , Ross EA , Jordan VC
Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time
Proc Natl Acad Sci U S A. 2011 Nov 22;108(47) :18879-86
PMID: 22011582    PMCID: PMC3223472    URL: http://www.ncbi.nlm.nih.gov/pubmed/22011582
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In laboratory studies, acquired resistance to long-term antihormonal therapy in breast cancer evolves through two phases over 5 y. Phase I develops within 1 y, and tumor growth occurs with either 17beta-estradiol (E(2)) or tamoxifen. Phase II resistance develops after 5 y of therapy, and tamoxifen still stimulates growth; however, E(2) paradoxically induces apoptosis. This finding is the basis for the clinical use of estrogen to treat advanced antihormone-resistant breast cancer. We interrogated E(2)-induced apoptosis by analysis of gene expression across time (2-96 h) in MCF-7 cell variants that were estrogen-dependent (WS8) or resistant to estrogen deprivation and refractory (2A) or sensitive (5C) to E(2)-induced apoptosis. We developed a method termed differential area under the curve analysis that identified genes uniquely regulated by E(2) in 5C cells compared with both WS8 and 2A cells and hence, were associated with E(2)-induced apoptosis. Estrogen signaling, endoplasmic reticulum stress (ERS), and inflammatory response genes were overrepresented among the 5C-specific genes. The identified ERS genes indicated that E(2) inhibited protein folding, translation, and fatty acid synthesis. Meanwhile, the ERS-associated apoptotic genes Bcl-2 interacting mediator of cell death (BIM; BCL2L11) and caspase-4 (CASP4), among others, were induced. Evaluation of a caspase peptide inhibitor panel showed that the CASP4 inhibitor z-LEVD-fmk was the most active at blocking E(2)-induced apoptosis. Furthermore, z-LEVD-fmk completely prevented poly (ADP-ribose) polymerase (PARP) cleavage, E(2)-inhibited growth, and apoptotic morphology. The up-regulated proinflammatory genes included IL, IFN, and arachidonic acid-related genes. Functional testing showed that arachidonic acid and E(2) interacted to superadditively induce apoptosis. Therefore, these data indicate that E(2) induced apoptosis through ERS and inflammatory responses in advanced antihormone-resistant breast cancer.
Ariazi, Eric A Cunliffe, Heather E Lewis-Wambi, Joan S Slifker, Michael J Willis, Amanda L Ramos, Pilar Tapia, Coya Kim, Helen R Yerrum, Smitha Sharma, Catherine G N Nicolas, Emmanuelle Balagurunathan, Yoganand Ross, Eric A Jordan, V Craig United States Proceedings of the National Academy of Sciences of the United States of America Proc Natl Acad Sci U S A. 2011 Nov 22;108(47):18879-86. Epub 2011 Oct 19.