Regulation of estrogen-mediated cell survival and proliferation by p160 coactivators

Christopher B. Weldon, Steven Elliott, Yun Zhu, John L. Clayton, Tyler J. Curiel, Bernard M. Jaffe, Matthew E. Burow

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15 Scopus citations

Abstract

Background Estrogen receptor (ER) activity is dependent on coactivator (CoA) proteins. The role of CoA-ER interactions in breast cancer apoptosis remains unexplored. Methods Expression vectors for the p160 CoA genes NCOA-1, NCOA-2, or NCOA-3 were transiently transfected into MCF-7 cells. Cell survival was determined by viability and clonogenic survival assays. Effects of CoA expression on estrogen (E2) signaling were determined by estrogen response element (ERE)-luciferase reporter-gene assay. Clonogenic and reporter-gene survival assays were used to examine the molecular inhibition of CoA function (dominant inhibitory [DI]-decoy-CoA) on cell survival. Statistical significance was established at the P < .05 level. Results Overexpression of NCOA-1, NCOA-2, and NCOA-3 enhanced E2-mediated gene expression by 3.17 ± 0.51-, 2.33 ± 0.8-, and 3.65 ± 0.65-fold, respectively, and enhanced cell survival by suppressing tumor necrosis factor alpha (TNF-α)-induced cell death from 80.23% ± 2.66% viability to 101.5% ± 8.9%, 86.9% ± 9.9%, and 95.7% ± 8.5% viability, respectively. NCOA-1 enhancement of cell survival occurred via suppression of TNF-α-induced apoptosis as confirmed by viability and morphologic evaluation. Clonogenic survival and E2-stimulated colony formation in MCF-7 cells were suppressed by expression of DI-decoy-NCOA-1 and DI-decoy-NCOA-3 to 34.4% ± 7.4% and 54% ± 5.4% of vector control, but not DI-decoy-NCOA-2. Conclusions Overexpression of NCOA-1 and NCOA-3 exerted potent survival effects in breast carcinoma cells. Use of DI-CoA constructs enhanced TNF-α-induced cell death and abrogated E2-induced survival. Inhibition of CoA proteins represents a mechanism for enhancing sensitivity therapies in breast carcinoma.

Original languageEnglish (US)
Pages (from-to)346-354
Number of pages9
JournalSurgery
Volume136
Issue number2
DOIs
Publication statusPublished - Aug 1 2004

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ASJC Scopus subject areas

  • Surgery

Cite this

Weldon, C. B., Elliott, S., Zhu, Y., Clayton, J. L., Curiel, T. J., Jaffe, B. M., & Burow, M. E. (2004). Regulation of estrogen-mediated cell survival and proliferation by p160 coactivators. Surgery, 136(2), 346-354. https://doi.org/10.1016/j.surg.2004.05.010