Gail E. Sonenshein
Professor of Biochemistry
Department of Biochemistry
Boston University School of Medicine
Silvio Conte Building, K615
72 E. Concord Street
Boston, MA 02118
Phone: 617-638-4120
Fax: 617-638-4252
Email: gsonensh@bu.edu
Education
B.S., Brooklyn Polytechnic Institute, NY
Ph.D., Massachusetts Institute of Technology, MA
Research Interest
Roles of the NF-kappaB transcription factor family and downstream mediators in promoting invasive cancer
The current research goals of my laboratory are to elucidate the mechanisms of activation and roles of the NF-kappaB (NF-kB) transcription factor family in breast cancer. Our laboratory was one of the first to show that NF-kB factors are aberrantly activated in breast cancer, and promote survival and invasive phenotype of these cells. Several oncogenes that have been implicated in breast cancer, including Her-2/neu and Ras, induce NF-kB. Thus, a major effort in the lab is to identify the signaling pathways and kinases mediating aberrant activation of NF-kB, including a new transcriptional pathway termed de novo RelB synthesis, as they represent potential therapeutic targets. We have prepared animal models to study the roles of the NF-kB, including the NF-kB c-Rel subunit, in breast cancer and mammary gland development. Using an MMTV-c-Rel mouse model, we showed that the NF-kB c-Rel subunit, which is activated in ~85% of human breast cancers, can play a causal role in mammary tumorigenesis. Bitransgenic MMTV-c-RelxCK2 mice develop highly invasive mammary tumors, and our work implicated the aryl hydrocarbon receptor and master regulator Slug in this phenotype. We have also elucidated a new mechanism for the late onset of the tumors that appear in the MMTV-c-Rel, which involves activation of PKCtheta and release of repression of c-Rel by estrogen receptor signaling. Studies are in progress to further identify the regulation and roles of NF-kB in neoplastic transformation induced by environmental carcinogens, including a new kinase IKKi implicated in invasive breast disease and the anti-carcinogenic effects of dietary factors such as the green tea polyphenol EGCG and 1,25-dihydroxyvitamin D3. We have also identified an inhibitor of activation of NF-kB by Her-2/neu and Ras in breast cancer: the pro-peptide domain of the enzyme Lysyl Oxidase (LOX-PP). Studies to test the efficacy of these inhibitors in vivo and to elucidate the mechanisms of their action are in progress. The overall goals are to aid in the development of improved treatment modalities for cancer.
Representative Publications
Campisi J, HE Gray, AB Pardee, M Dean, GE Sonenshein. Cell cycle control of c-myc but not c-ras
expression is lost following chemical transformation. Cell 36:241-47 (1984) [PMID: 6692471].
Wu, M, H Lee, RE Bellas, SL Schauer, M Arsura, D Katz, M FitzGerald, TL Rothstein, DH Sherr, GE
Sonenshein. Inhibition of NF-kB/Rel induces apoptosis of murine B cells. EMBO J. 15:4682-90 (1996)
[PMCID: PMC452200].
Sovak MA, RE Bellas, DW Kim, GJ Zanieski, AE Rogers, AM Traish, GE Sonenshein. Aberrant NF-kB/Rel
expression and the pathogenesis of breast cancer. J Clin Investig. 100:2952-60 (1997) [PMCID:
PMC508506].
Kim DW, MA Sovak, G Zanieski, G Nonet, R Romieu-Mourez, AW Lau, LJ Hafer, P Yaswen, M Stampfer, AE Rogers, J Russo, GE Sonenshein. Activation of NF-kB/Rel occurs early during neoplastic transformation of mammary cells. Carcinogenesis 21:871-9 (2000) [PMID: 10783306].
Pianetti S, M Arsura, R Romieu-Mourez, R Coffey, GE Sonenshein. Her-2/neu overexpression induces NF-kB via a PI3-kinase/Akt pathway without IKK activation that can be inhibited by the tumor suppressor PTEN. Oncogene 20:1287-99 (2001) [PMID: 11313873].
Kavanagh KT, LJ Hafer, DW Kim, KK Mann, DH Sherr, AE Rogers, GE Sonenshein. Green tea extracts
decrease carcinogen-induced mammary tumor burden in rats and rate of breast cancer cell proliferation in culture. J Cell Biochem. 82:387-98 (2001) [PMID: 11500915].
Pianetti, S, S Guo, KT Kavanagh, GE Sonenshein. Green tea polyphenol epigallocatechin-3 gallate inhibits
Her-2/neu signaling, proliferation and transformed phenotype of breast cancer cells. Cancer Research
62:652-55 (2002) [PMID: 11830514].
Jeay, S, S Pianetti, HM Kagan, GE Sonenshein. Lysyl oxidase inhibits Ras-mediated transformation by
preventing activation of NF-kB. Mol. Cell. Biol. 23:2251-63 (2003) [PMCID: PMC150722].
Romieu-Mourez, R, DW Kim, SM Shin, EG Demicco, E Landesman-Bollag, DC Seldin, RD Cardiff, GE
Sonenshein. MMTV-c-rel transgenic mice develop mammary tumors. Mol Cell Biol. 23:5738-54 (2003)
[PMCID: PMC166341].
Palamakumbura, AH, S Jeay, Y Guo, N Pischon, P Sommer, GE Sonenshein, PC Trackman. The pro-peptide domain of lysyl oxidase induces phenotypic reversion of Ras-transformed cells. J. Biol. Chem. 279:40593-600 (2004) [PMID: 15277520].
Guo, S, GE Sonenshein. Forkhead box transcription factor FOXO3a regulates ERa expression and is repressed by the Her-2/neu/PI3K/Akt signaling pathway. Mol Cell Biol. 24:8681-90 (2004)[ PMCID: PMC516736].
Wang, X, GE Sonenshein. Induction of the RelB NF-kB subunit by the Cytomegalovirus IE1 protein is
mediated via Jun kinase and c-Jun/Fra-2 AP-1 complexes. J. Virol. 79:95-105 (2005) [PMCID: PMC538727].
Demicco, EG, KT Kavanagh, R Romieu-Mourez, X Wang, SR Shin, E Landesman-Bollag, DC Seldin, GE Sonenshein. RelB/p52 NF-κB complexes rescue an early delay in mammary gland development in transgenic mice with targeted super-repressor IkB-a expression and promote carcinogenesis of the mammary gland. Mol. Cell Biol. 25:10136-47 (2005) [PMCID: PMC1280249].
Guo, S, S Yang, C Taylor, GE Sonenshein. Green tea polyphenol epigallocatechin-3 gallate (EGCG) affects
gene expression of breast cancer cells transformed by the carcinogen 7,12-dimethylbenz[a]anthracene. J. Nutrition 135: 2978S-86S (2005) [PMID: 16317158].
Eddy, S, S Guo, EG Dimecco, R Romieu-Mourez, E Landesman-Bollag, D Seldin, GE. Sonenshein. IKK-i/IKKe expression is induced by CK2 and promotes aberrant NF-kB activation in breast cancer cells. Cancer Res 65:11375-83 (2005) [ PMID: 16357145].
Shin SR, N Sánchez-Velar, DH Sherr, GE Sonenshein. 7,12-Dimethylbenz[a]anthracene treatment of a c-rel mouse mammary tumor cell line induces epithelial to mesenchymal transition via activation of NF-kB. Cancer Res. 66:2750-5 (2006) [PMID: 16510574].
Min C, KH Kirsch, Y Zhao, S Jeay, AH Palamakumbura, PC Trackman, GE Sonenshein. The tumor
suppressor activity of the lysyl oxidase pro-peptide reverses invasive phenotype of Her-2/neu driven breast cancer. Cancer Res 67: 1105-12 (2007) [PMID: 17283144].
Wang, X, K Belguise, N Kersual, KH Kirsch, ND Mineva, F Galtier, D Chalbos, GE Sonenshein. Inhibition of de novo RelB synthesis by ERα signaling in breast cancer cells: a novel mechanism controlling epithelial to mesenchymal transition using Bcl-2 as mediator. Nature Cell Biol. 9:470-78 (2007) [PMCID: PMC2394707]
Belguise, K, S Guo, GE Sonenshein. Activation of FOXO3a by the green tea polyphenol epigallocatechin-3-gallate induces estrogen receptor a expression reversing invasive phenotype of breast cancer cells. Cancer Res 67: 5763-70 (2007) [PMID: 17575143].
Wu, M, C Min, X Wang, Z Yu, KH Kirsch, PC Trackman, GE Sonenshein. Repression of BCL2 by the tumor
suppressor activity of the lysyl oxidase pro-peptide inhibits transformed phenotype of lung and pancreatic cancer cells. Cancer Research 67:6278-85 (2007) [PMID: 17616686].
Eddy, SF., SE Kane and GE Sonenshein. Trastuzumab resistant HER2-driven breast cancer cells are sensitive to epigallocatechin-3 gallate. Cancer Res. 67:9018-23 (2007) [PMID: 17909003].
Belguise, K and GE Sonenshein. PKCθ to Akt pathway promotes c-Rel-driven mammary tumorigenesis by repressing FOXO3a-induced ERa synthesis. J. Clinical Invest. 117:4009-21 (2007) [PMCID: PMC2082145].
Belguise, K, S Guo, S Yang, AE Rogers, DC Seldin, DH Sherr, GE Sonenshein. Green tea polyphenols
reverse cooperation between c-Rel and CK2 that activates the AhR, Slug and invasive phenotype. Cancer
Res. 67:11742-50 (2007) [PMID: 18089804].
Min, C, SF Eddy, DH Sherr, GE Sonenshein. NF-kB and epithelial to mesenchymal transition of cancer. J. Cell. Biochem. 104:733-44 (2008) [PMID: 18253935].
Zhao, Y, C Min, S Vora, PC Trackman, GE Sonenshein, KH Kirsch. The lysyl oxidase pro-peptide attenuates fibronectin-mediated activation of FAK and p130CAS in breast cancer cells. J. Biol. Chem. 284:1385-93 (2009) 2008 Nov 21. [Epub ahead of print]. [PMID: 19029090]
Mineva, N, X Wang, S Yang, H Ying, J Xiao, MF Holick, GE Sonenshein. Inhibition of RelB by 1,25-
Dihydroxyvitamin D3 promotes sensitivity of breast cancer cells to radiation. J. Cell Physiol (in press).
