Hostname: page-component-78c5997874-mlc7c Total loading time: 0 Render date: 2024-11-08T10:33:17.524Z Has data issue: false hasContentIssue false

CCAAT/enhancer-binding protein β: its role in breast cancer and associations with receptor tyrosine kinases

Published online by Cambridge University Press:  08 April 2009

Cynthia A. Zahnow*
Affiliation:
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Bunting-Blaustein Cancer Research Building, 1650 Orleans St, Baltimore, MD 21231-1000, USA. Tel: +1 410 955 8506; Fax: +1 410 614 9884; E-mail: [email protected]

Abstract

The CCAAT/enhancer-binding proteins (C/EBPs) are a family of leucine-zipper transcription factors that regulate gene expression to control cellular proliferation, differentiation, inflammation and metabolism. Encoded by an intronless gene, C/EBPβ is expressed as several distinct protein isoforms (LAP1, LAP2, LIP) whose expression is regulated by the differential use of several in-frame translation start sites. LAP1 and LAP2 are transcriptional activators and are associated with differentiation, whereas LIP is frequently elevated in proliferative tissue and acts as a dominant-negative inhibitor of transcription. However, emerging evidence suggests that LIP can serve as a transcriptional activator in some cellular contexts, and that LAP1 and LAP2 might also have unique actions. The LIP:LAP ratio is crucial for the maintenance of normal growth and development, and increases in this ratio lead to aggressive forms of breast cancer. This review discusses the regulation of C/EBPβ activity by post-translational modification, the individual actions of LAP1, LAP2 and LIP, and the functions and downstream targets that are unique to each isoform. The role of the C/EBPβ isoforms in breast cancer is discussed and emphasis is placed on their interactions with receptor tyrosine kinases.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Cao, Z., Umek, R.M. and McKnight, S.L. (1991) Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes and Development 5, 1538-1552CrossRefGoogle ScholarPubMed
2Diehl, A.M. (1998) Roles of CCAAT/enhancer-binding proteins in regulation of liver regenerative growth. Journal of Biological Chemistry 273, 30843-30846CrossRefGoogle ScholarPubMed
3Poli, V. (1998) The role of C/EBP isoforms in the control of inflammatory and native immunity functions. Journal of Biological Chemistry 273, 29279-29282CrossRefGoogle ScholarPubMed
4Zahnow, C.A. (2002) CCAAT/enhancer binding proteins in normal mammary development and breast cancer. Breast Cancer Research 4, 113-121CrossRefGoogle ScholarPubMed
5Ramji, D.P. and Foka, P. (2002) CCAAT/enhancer-binding proteins: structure, function and regulation. Biochemical Journal 365, 561-575CrossRefGoogle ScholarPubMed
6Sebastian, T. and Johnson, P.F. (2006) Stop and go: anti-proliferative and mitogenic functions of the transcription factor C/EBPbeta. Cell Cycle 5, 953-957CrossRefGoogle ScholarPubMed
7Kowenz-Leutz, E. et al. (1994) Novel mechanism of C/EBP beta (NF-M) transcriptional control: activation through derepression. Genes and Development 8, 2781-2791CrossRefGoogle ScholarPubMed
8Williams, S.C. et al. (1995) CRP2 (C/EBP beta) contains a bipartite regulatory domain that controls transcriptional activation, DNA binding and cell specificity. EMBO Journal 14, 3170-3183CrossRefGoogle ScholarPubMed
9Angerer, N.D. et al. (1999) A short conserved motif is required for repressor domain function in the myeloid-specific transcription factor CCAAT/enhancer-binding protein epsilon. Journal of Biological Chemistry 274, 4147-4154CrossRefGoogle Scholar
10Williamson, E.A. et al. (1998) Identification of transcriptional activation and repression domains in human CCAAT/enhancer-binding protein epsilon. Journal of Biological Chemistry 273, 14796-14804CrossRefGoogle ScholarPubMed
11Mink, S., Haenig, B. and Klempnauer, K.H. (1997) Interaction and functional collaboration of p300 and C/EBPbeta. Molecular and Cellular Biology 17, 6609-6617CrossRefGoogle ScholarPubMed
12Nerlov, C. and Ziff, E.B. (1995) CCAAT/enhancer binding protein-alpha amino acid motifs with dual TBP and TFIIB binding ability co-operate to activate transcription in both yeast and mammalian cells. EMBO Journal 14, 4318-4328CrossRefGoogle ScholarPubMed
13Graves, B.J., Johnson, P.F. and McKnight, S.L. (1986) Homologous recognition of a promoter domain common to the MSV LTR and the HSV tk gene. Cell 44, 565-576CrossRefGoogle Scholar
14Johnson, P.F. et al. (1987) Identification of a rat liver nuclear protein that binds to the enhancer core element of three animal viruses. Genes and Development 1, 133-146CrossRefGoogle Scholar
15Landschulz, W.H. et al. (1988) Isolation of a recombinant copy of the gene encoding C/EBP. Genes and Development 2, 786-800CrossRefGoogle ScholarPubMed
16Descombes, P. et al. (1990) LAP, a novel member of the C/EBP gene family, encodes a liver-enriched transcriptional activator protein. Genes and Development 4, 1541-1551CrossRefGoogle Scholar
17Chang, C.J. et al. (1990) Molecular cloning of a transcription factor, AGP/EBP, that belongs to members of the C/EBP family. Molecular and Cellular Biology 10, 6642-6653Google ScholarPubMed
18Akira, S. et al. (1990) A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO Journal 9, 1897-1906CrossRefGoogle ScholarPubMed
19Poli, V., Mancini, F.P. and Cortese, R. (1990) IL-6DBP, a nuclear protein involved in interleukin-6 signal transduction, defines a new family of leucine zipper proteins related to C/EBP. Cell 63, 643-653CrossRefGoogle ScholarPubMed
20Descombes, P. and Schibler, U. (1991) A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA. Cell 67, 569-579CrossRefGoogle Scholar
21Ossipow, V., Descombes, P. and Schibler, U. (1993) CCAAT/enhancer-binding protein mRNA is translated into multiple proteins with different transcription activation potentials. Proceedings of the National Academy of Sciences of the United States of America 90, 8219-8223CrossRefGoogle ScholarPubMed
22Calkhoven, C.F., Muller, C. and Leutz, A. (2000) Translational control of C/EBPalpha and C/EBPbeta isoform expression. Genes and Development 14, 1920-1932CrossRefGoogle ScholarPubMed
23Xiong, W. et al. (2001) Regulation of CCAAT/enhancer-binding protein-beta isoform synthesis by alternative translational initiation at multiple AUG start sites. Nucleic Acids Research 29, 3087-3098CrossRefGoogle ScholarPubMed
24Lin, F.T. et al. (1993) A 30-kDa alternative translation product of the CCAAT/enhancer binding protein alpha message: transcriptional activator lacking antimitotic activity. Proceedings of the National Academy of Sciences of the United States of America 90, 9606-9610CrossRefGoogle ScholarPubMed
25Welm, A.L., Timchenko, N.A. and Darlington, G.J. (1999) C/EBPalpha regulates generation of C/EBPbeta isoforms through activation of specific proteolytic cleavage. Molecular and Cellular Biology 19, 1695-1704CrossRefGoogle ScholarPubMed
26Yamanaka, R. et al. (1997) CCAAT/enhancer binding protein epsilon is preferentially up-regulated during granulocytic differentiation and its functional versatility is determined by alternative use of promoters and differential splicing. Proceedings of the National Academy of Sciences of the United States of America 94, 6462-6467CrossRefGoogle ScholarPubMed
27Vinson, C.R., Sigler, P.B. and McKnight, S.L. (1989) Scissors-grip model for DNA recognition by a family of leucine zipper proteins. Science 246, 911-916CrossRefGoogle ScholarPubMed
28Agre, P., Johnson, P.F. and McKnight, S.L. (1989) Cognate DNA binding specificity retained after leucine zipper exchange between GCN4 and C/EBP. Science 246, 922-926CrossRefGoogle ScholarPubMed
29Moll, J.R. et al. (2002) Magnesium is required for specific DNA binding of the CREB B-ZIP domain. Nucleic Acids Research 30, 1240-1246CrossRefGoogle ScholarPubMed
30Osada, S. et al. (1996) DNA binding specificity of the CCAAT/enhancer-binding protein transcription factor family. Journal of Biological Chemistry 271, 3891-3896CrossRefGoogle ScholarPubMed
31Ron, D. and Habener, J.F. (1992) CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Genes and Development 6, 439-453CrossRefGoogle Scholar
32Ubeda, M. et al. (1996) Stress-induced binding of the transcriptional factor CHOP to a novel DNA control element. Molecular and Cellular Biology 16, 1479-1489CrossRefGoogle ScholarPubMed
33Cooper, C. et al. (1995) Ig/EBP (C/EBP gamma) is a transdominant negative inhibitor of C/EBP family transcriptional activators. Nucleic Acids Research 23, 4371-4377CrossRefGoogle ScholarPubMed
34Lekstrom-Himes, J.A. (2001) The role of C/EBP(epsilon) in the terminal stages of granulocyte differentiation. Stem Cells 19, 125-133CrossRefGoogle ScholarPubMed
35Grimm, S.L. and Rosen, J.M. (2003) The role of C/EBPbeta in mammary gland development and breast cancer. Journal of Mammary Gland Biology and Neoplasia 8, 191-204CrossRefGoogle ScholarPubMed
36Vinson, C. et al. (2002) Classification of human B-ZIP proteins based on dimerization properties. Molecular and Cellular Biology 22, 6321-6335CrossRefGoogle ScholarPubMed
37Takiguchi, M. (1998) The C/EBP family of transcription factors in the liver and other organs. International Journal of Experimental Pathology 79, 369-391CrossRefGoogle Scholar
38Nakajima, T. et al. (1993) Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6. Proceedings of the National Academy of Sciences of the United States of America 90, 2207-2211CrossRefGoogle ScholarPubMed
39Zhu, S. et al. (2002) CCAAT/enhancer binding protein-beta is a mediator of keratinocyte survival and skin tumorigenesis involving oncogenic Ras signaling. Proceedings of the National Academy of Sciences of the United States of America 99, 207-212CrossRefGoogle ScholarPubMed
40Mo, X. et al. (2004) Ras induces mediator complex exchange on C/EBP beta. Molecular Cell 13, 241-250CrossRefGoogle ScholarPubMed
41Liao, J. et al. (1999) CCAAT/enhancer-binding protein beta (C/EBPbeta) and C/EBPdelta contribute to growth hormone-regulated transcription of c-fos. Journal of Biological Chemistry 274, 31597-31604CrossRefGoogle Scholar
42Piwien-Pilipuk, G. et al. (2001) Growth hormone regulates phosphorylation and function of CCAAT/enhancer-binding protein beta by modulating Akt and glycogen synthase kinase-3. Journal of Biological Chemistry 276, 19664-19671CrossRefGoogle ScholarPubMed
43Tang, Q.Q. et al. (2005) Sequential phosphorylation of CCAAT enhancer-binding protein beta by MAPK and glycogen synthase kinase 3beta is required for adipogenesis. Proceedings of the National Academy of Sciences of the United States of America 102, 9766-9771CrossRefGoogle ScholarPubMed
44Wegner, M., Cao, Z. and Rosenfeld, M.G. (1992) Calcium-regulated phosphorylation within the leucine zipper of C/EBP beta. Science 256, 370-373CrossRefGoogle ScholarPubMed
45Buck, M. et al. (1999) Phosphorylation of rat serine 105 or mouse threonine 217 in C/EBP beta is required for hepatocyte proliferation induced by TGF alpha. Molecular Cell 4, 1087-1092CrossRefGoogle ScholarPubMed
46Buck, M. et al. (2001) C/EBPbeta phosphorylation by RSK creates a functional XEXD caspase inhibitory box critical for cell survival. Molecular Cell 8, 807-816CrossRefGoogle ScholarPubMed
47Metz, R. and Ziff, E. (1991) cAMP stimulates the C/EBP-related transcription factor rNFIL-6 to trans-locate to the nucleus and induce c-fos transcription. Genes and Development 5, 1754-1766CrossRefGoogle Scholar
48Trautwein, C. et al. (1993) Transactivation by NF-IL6/LAP is enhanced by phosphorylation of its activation domain. Nature 364, 544-547CrossRefGoogle ScholarPubMed
49Trautwein, C. et al. (1994) Protein kinase A and C site-specific phosphorylations of LAP (NF-IL6) modulate its binding affinity to DNA recognition elements. Journal of Clinical Investigation 93, 2554-2561CrossRefGoogle Scholar
50Mahoney, C.W. et al. (1992) Phosphorylation of CCAAT-enhancer binding protein by protein kinase C attenuates site-selective DNA binding. Journal of Biological Chemistry 267, 19396-19403CrossRefGoogle ScholarPubMed
51Chinery, R. et al. (1997) Antioxidant-induced nuclear translocation of CCAAT/enhancer-binding protein beta. A critical role for protein kinase A-mediated phosphorylation of Ser299. Journal of Biological Chemistry 272, 30356-30361CrossRefGoogle ScholarPubMed
52Shuman, J.D. et al. (2004) Cell cycle-dependent phosphorylation of C/EBPbeta mediates oncogenic cooperativity between C/EBPbeta and H-RasV12. Molecular and Cellular Biology 24, 7380-7391CrossRefGoogle ScholarPubMed
53Cesena, T.I. et al. (2007) CCAAT/enhancer-binding protein (C/EBP) beta is acetylated at multiple lysines: acetylation of C/EBPbeta at lysine 39 modulates its ability to activate transcription. Journal of Biological Chemistry 282, 956-967CrossRefGoogle ScholarPubMed
54Cesena, T.I. et al. (2008) Acetylation and deacetylation regulate CCAAT/enhancer binding protein beta at K39 in mediating gene transcription. Molecular and Cellular Endocrinology 289, 94-101CrossRefGoogle ScholarPubMed
55Wiper-Bergeron, N. et al. (2007) Glucocorticoid-stimulated preadipocyte differentiation is mediated through acetylation of C/EBPbeta by GCN5. Proceedings of the National Academy of Sciences of the United States of America 104, 2703-2708CrossRefGoogle ScholarPubMed
56Xu, M. et al. (2003) STAT5-induced Id-1 transcription involves recruitment of HDAC1 and deacetylation of C/EBPbeta. EMBO Journal 22, 893-904CrossRefGoogle ScholarPubMed
57Pless, O. et al. (2008) G9a-mediated lysine methylation alters the function of CCAAT/enhancer-binding protein-beta. Journal of Biological Chemistry 283, 26357-26363CrossRefGoogle ScholarPubMed
58Melchior, F. (2000) SUMO–nonclassical ubiquitin. Annual Review of Cell and Developmental Biology 16, 591-626CrossRefGoogle ScholarPubMed
59Eaton, E.M. and Sealy, L. (2003) Modification of CCAAT/enhancer-binding protein-beta by the small ubiquitin-like modifier (SUMO) family members, SUMO-2 and SUMO-3. Journal of Biological Chemistry 278, 33416-33421CrossRefGoogle ScholarPubMed
60Berberich-Siebelt, F. et al. (2006) SUMOylation interferes with CCAAT/enhancer-binding protein beta-mediated c-myc repression, but not IL-4 activation in T cells. Journal of Immunology 176, 4843-4851CrossRefGoogle Scholar
61Kowenz-Leutz, E. and Leutz, A. (1999) A C/EBP beta isoform recruits the SWI/SNF complex to activate myeloid genes. Molecular Cell 4, 735-743CrossRefGoogle Scholar
62Ness, S.A. et al. (1993) Myb and NF-M: combinatorial activators of myeloid genes in heterologous cell types. Genes and Development 7, 749-759CrossRefGoogle ScholarPubMed
63Burk, O. et al. (1993) Synergistic activation of the chicken mim-1 gene by v-myb and C/EBP transcription factors. EMBO Journal 12, 2027-2038CrossRefGoogle ScholarPubMed
64Su, W.C. et al. (2003) Differential activation of a C/EBP beta isoform by a novel redox switch may confer the lipopolysaccharide-inducible expression of interleukin-6 gene. Journal of Biological Chemistry 278, 51150-51158CrossRefGoogle Scholar
65Qiu, X. et al. (2008) Distinct functions of CCAAT enhancer-binding protein isoforms in the regulation of manganese superoxide dismutase during interleukin-1beta stimulation. Journal of Biological Chemistry 283, 25774-25785CrossRefGoogle ScholarPubMed
66Eaton, E.M. et al. (2001) Characterization of C/EBPbeta isoforms in normal versus neoplastic mammary epithelial cells. Journal of Cellular Physiology 189, 91-105CrossRefGoogle ScholarPubMed
67Ishiguro, K. and Xavier, R. (2004) Homer-3 regulates activation of serum response element in T cells via its EVH1 domain. Blood 103, 2248-2256CrossRefGoogle Scholar
68Lee, Y.M. et al. (1996) Transcriptional induction of the alpha-1 acid glycoprotein (AGP) gene by synergistic interaction of two alternative activator forms of AGP/enhancer-binding protein (C/EBP beta) and NF-kappaB or Nopp140. Molecular and Cellular Biology 16, 4257-4263CrossRefGoogle ScholarPubMed
69Zahnow, C.A. et al. (2001) A role for CCAAT/enhancer binding protein beta-liver-enriched inhibitory protein in mammary epithelial cell proliferation. Cancer Research 61, 261-269Google ScholarPubMed
70Harrison, J.R. et al. (2005) Col1a1 promoter-targeted expression of p20 CCAAT enhancer-binding protein beta (C/EBPbeta), a truncated C/EBPbeta isoform, causes osteopenia in transgenic mice. Journal of Biological Chemistry 280, 8117-8124CrossRefGoogle ScholarPubMed
71Savage, T. et al. (2006) Mandibular phenotype of p20C/EBPbeta transgenic mice: Reduced alveolar bone mass and site-specific dentin dysplasia. Bone 39, 552-564CrossRefGoogle ScholarPubMed
72An, M.R. et al. (1996) Evidence for posttranscriptional regulation of C/EBPalpha and C/EBPbeta isoform expression during the lipopolysaccharide-mediated acute-phase response. Molecular and Cellular Biology 16, 2295-2306CrossRefGoogle Scholar
73Williams, P. et al. (1991) AGP/EBP(LAP) expressed in rat hepatoma cells interacts with multiple promoter sites and is necessary for maximal glucocorticoid induction of the rat alpha-1 acid glycoprotein gene. Molecular and Cellular Biology 11, 4959-4965Google ScholarPubMed
74Ratajczak, T. et al. (1992) Multiple elements within the glucocorticoid regulatory unit of the rat alpha 1-acid glycoprotein gene are recognition sites for C/EBP. Journal of Biological Chemistry 267, 11111-11119CrossRefGoogle ScholarPubMed
75Nishio, Y. et al. (1993) A nuclear factor for interleukin-6 expression (NF-IL6) and the glucocorticoid receptor synergistically activate transcription of the rat alpha 1-acid glycoprotein gene via direct protein-protein interaction. Molecular and Cellular Biology 13, 1854-1862Google ScholarPubMed
76Isshiki, H. et al. (1990) Constitutive and interleukin-1 (IL-1)-inducible factors interact with the IL-1-responsive element in the IL-6 gene. Molecular and Cellular Biology 10, 2757-2764Google ScholarPubMed
77Hu, H.M. et al. (2000) The C/EBP bZIP domain can mediate lipopolysaccharide induction of the proinflammatory cytokines interleukin-6 and monocyte chemoattractant protein-1. Journal of Biological Chemistry 275, 16373-16381CrossRefGoogle Scholar
78Matsusaka, T. et al. (1993) Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proceedings of the National Academy of Sciences of the United States of America 90, 10193-10197CrossRefGoogle ScholarPubMed
79Stein, B., Cogswell, P.C. and Baldwin, A.S. Jr. (1993) Functional and physical associations between NF-kappa B and C/EBP family members: a Rel domain-bZIP interaction. Molecular and Cellular Biology 13, 3964-3974Google Scholar
80Christian, M. et al. (2002) Functional association of PR and CCAAT/enhancer-binding protein beta isoforms: promoter-dependent cooperation between PR-B and liver-enriched inhibitory protein, or liver-enriched activatory protein and PR-A in human endometrial stromal cells. Molecular Endocrinology 16, 141-154Google ScholarPubMed
81Kalkhoven, E. et al. (1996) Negative interaction between the RelA(p65) subunit of NF-kappaB and the progesterone receptor. Journal of Biological Chemistry 271, 6217-6224CrossRefGoogle ScholarPubMed
82Hata, K. et al. (2005) A CCAAT/enhancer binding protein beta isoform, liver-enriched inhibitory protein, regulates commitment of osteoblasts and adipocytes. Molecular and Cellular Biology 25, 1971-1979CrossRefGoogle ScholarPubMed
83Tang, Q.Q., Otto, T.C. and Lane, M.D. (2003) CCAAT/enhancer-binding protein beta is required for mitotic clonal expansion during adipogenesis. Proceedings of the National Academy of Sciences of the United States of America 100, 850-855CrossRefGoogle ScholarPubMed
84Vegesna, V. et al. (2002) C/EBP-beta, C/EBP-delta, PU.1, AML1 genes: mutational analysis in 381 samples of hematopoietic and solid malignancies. Leukemia Research 26, 451-457CrossRefGoogle ScholarPubMed
85Mastracci, T.L. et al. (2006) Genomic alterations in lobular neoplasia: a microarray comparative genomic hybridization signature for early neoplastic proliferationin the breast. Genes, Chromosomes and Cancer 45, 1007-1017CrossRefGoogle ScholarPubMed
86Rhodes, D.R. et al. (2004) ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6, 1-6CrossRefGoogle ScholarPubMed
87Alaoui-Jamali, M.A. et al. (2003) Regulation of multiple tumor microenvironment markers by overexpression of single or paired combinations of ErbB receptors. Cancer Research 63, 3764-3774Google ScholarPubMed
88van't Veer, L.J. et al. (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530-536CrossRefGoogle ScholarPubMed
89Gruvberger, S. et al. (2001) Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns. Cancer Research 61, 5979-5984Google ScholarPubMed
90van de Vijver, M.J. et al. (2002) A gene-expression signature as a predictor of survival in breast cancer. New England Journal of Medicine 347, 1999-2009CrossRefGoogle ScholarPubMed
91Yang, F. et al. (2006) Laser microdissection and microarray analysis of breast tumors reveal ER-alpha related genes and pathways. Oncogene 25, 1413-1419CrossRefGoogle ScholarPubMed
92Saal, L.H. et al. (2007) Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proceedings of the National Academy of Sciences of the United States of America 104, 7564-7569CrossRefGoogle ScholarPubMed
93Finak, G. et al. (2008) Stromal gene expression predicts clinical outcome in breast cancer. Nature Medicine 14, 518-527CrossRefGoogle ScholarPubMed
94Ma, X.J. et al. (2004) A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell 5, 607-616CrossRefGoogle ScholarPubMed
95Zahnow, C.A. et al. (1997) Overexpression of C/EBPbeta-LIP, a naturally occurring, dominant-negative transcription factor, in human breast cancer. Journal of the National Cancer Institute 89, 1887-1891Google ScholarPubMed
96Milde-Langosch, K., Loning, T. and Bamberger, A.M. (2003) Expression of the CCAAT/enhancer-binding proteins C/EBPalpha, C/EBPbeta and C/EBPdelta in breast cancer: correlations with clinicopathologic parameters and cell-cycle regulatory proteins. Breast Cancer Research and Treatment 79, 175-185CrossRefGoogle Scholar
97Gomis, R.R. et al. (2006) C/EBPbeta at the core of the TGFbeta cytostatic response and its evasion in metastatic breast cancer cells. Cancer Cell 10, 203-214CrossRefGoogle ScholarPubMed
98Seagroves, T.N. et al. (1998) C/EBPbeta, but not C/EBPalpha, is essential for ductal morphogenesis, lobuloalveolar proliferation, and functional differentiation in the mouse mammary gland. Genes and Development 12, 1917-1928CrossRefGoogle Scholar
99Robinson, G.W. et al. (1998) The C/EBPbeta transcription factor regulates epithelial cell proliferation and differentiation in the mammary gland. Genes and Development 12, 1907-1916CrossRefGoogle Scholar
100Seagroves, T.N. et al. (2000) C/EBPbeta (CCAAT/enhancer binding protein) controls cell fate determination during mammary gland development. Molecular Endocrinology 14, 359-368Google ScholarPubMed
101Uematsu, S. et al. (2007) The C/EBP beta isoform 34-kDa LAP is responsible for NF-IL-6-mediated gene induction in activated macrophages, but is not essential for intracellular bacteria killing. Journal of Immunology 179, 5378-5386CrossRefGoogle Scholar
102Baldwin, B.R., Timchenko, N.A. and Zahnow, C.A. (2004) Epidermal Growth Factor Receptor Stimulation Activates the RNA Binding Protein CUG-BP1 and Increases Expression of C/EBPbeta-LIP in Mammary Epithelial Cells. Molecular and Cellular Biology 24, 3682-3691CrossRefGoogle ScholarPubMed
103Bundy, L.M. and Sealy, L. (2003) CCAAT/enhancer binding protein beta (C/EBPbeta)-2 transforms normal mammary epithelial cells and induces epithelial to mesenchymal transition in culture. Oncogene 22, 869-883CrossRefGoogle ScholarPubMed
104Zhou, J. et al. (2001) Malignant breast epithelial cells stimulate aromatase expression via promoter II in human adipose fibroblasts: an epithelial-stromal interaction in breast tumors mediated by CCAAT/enhancer binding protein beta. Cancer Research 61, 2328-2334Google Scholar
105Combates, N.J. et al. (1994) NF-IL6, a member of the C/EBP family of transcription factors, binds and trans-activates the human MDR1 gene promoter. Journal of Biological Chemistry 269, 29715-29719CrossRefGoogle Scholar
106Conze, D. et al. (2001) Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells. Cancer Research 61, 8851-8858Google ScholarPubMed
107Chen, G.K. et al. (2004) CCAAT/enhancer-binding protein beta (nuclear factor for interleukin 6) transactivates the human MDR1 gene by interaction with an inverted CCAAT box in human cancer cells. Molecular Pharmacology 65, 906-916CrossRefGoogle ScholarPubMed
108Leonessa, F. and Clarke, R. (2003) ATP binding cassette transporters and drug resistance in breast cancer. Endocrine-Related Cancer 10, 43-73CrossRefGoogle ScholarPubMed
109Wessells, J., Yakar, S. and Johnson, P.F. (2004) Critical prosurvival roles for C/EBP beta and insulin-like growth factor I in macrophage tumor cells. Molecular and Cellular Biology 24, 3238-3250CrossRefGoogle ScholarPubMed
110Yoon, K. et al. (2007) Decreased survival of C/EBP beta-deficient keratinocytes is due to aberrant regulation of p53 levels and function. Oncogene 26, 360-367CrossRefGoogle ScholarPubMed
111Ewing, S.J. et al. (2008) C/EBPbeta represses p53 to promote cell survival downstream of DNA damage independent of oncogenic Ras and p19(Arf). Cell Death and Differentiation 15, 1734-1744CrossRefGoogle ScholarPubMed
112Buck, M., Turler, H. and Chojkier, M. (1994) LAP (NF-IL-6), a tissue-specific transcriptional activator, is an inhibitor of hepatoma cell proliferation. EMBO Journal 13, 851-860CrossRefGoogle ScholarPubMed
113Zhu, S. et al. (1999) C/EBPbeta modulates the early events of keratinocyte differentiation involving growth arrest and keratin 1 and keratin 10 expression. Molecular and Cellular Biology 19, 7181-7190CrossRefGoogle ScholarPubMed
114Johnson, P.F. (2005) Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors. Journal of Cell Science 118, 2545-2555CrossRefGoogle ScholarPubMed
115Sebastian, T. et al. (2005) C/EBPbeta cooperates with RB:E2F to implement Ras(V12)-induced cellular senescence. EMBO Journal 24, 3301-3312CrossRefGoogle ScholarPubMed
116Acosta, J.C. et al. (2008) Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006-1018CrossRefGoogle ScholarPubMed
117Kuilman, T. et al. (2008) Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019-1031CrossRefGoogle ScholarPubMed
118Schlessinger, J. (2002) Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell 110, 669-672CrossRefGoogle ScholarPubMed
119Hynes, N.E. and Lane, H.A. (2005) ERBB receptors and cancer: the complexity of targeted inhibitors. Nature Reviews. Cancer 5, 341-354CrossRefGoogle ScholarPubMed
120Zahnow, C.A. (2006) ErbB receptors and their ligands in the breast. Expert Rev Molecular Medicine 8, 1-21CrossRefGoogle ScholarPubMed
121Walker, R.A. and Dearing, S.J. (1999) Expression of epidermal growth factor receptor mRNA and protein in primary breast carcinomas. Breast Cancer Research and Treatment 53, 167-176CrossRefGoogle ScholarPubMed
122Di Fiore, P.P. et al. (1987) erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science 237, 178-182CrossRefGoogle ScholarPubMed
123Allred, D.C. et al. (1992) Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer. Human Pathology 23, 974-979CrossRefGoogle ScholarPubMed
124Arcidiacono, M.V. et al. (2008) EGFR activation increases parathyroid hyperplasia and calcitriol resistance in kidney disease. Journal of the American Society of Nephrology 19, 310-320CrossRefGoogle ScholarPubMed
125He, D. et al. (2008) Lysophosphatidic acid-induced transactivation of epidermal growth factor receptor regulates cyclo-oxygenase-2 expression and prostaglandin E(2) release via C/EBPbeta in human bronchial epithelial cells. Biochemical Journal 412, 153-162CrossRefGoogle Scholar
126Dickson, C. et al. (2000) Tyrosine kinase signalling in breast cancer: fibroblast growth factors and their receptors. Breast Cancer Research 2, 191-196CrossRefGoogle ScholarPubMed
127Eswarakumar, V.P., Lax, I. and Schlessinger, J. (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine and Growth Factor Reviews 16, 139-149CrossRefGoogle ScholarPubMed
128Klagsbrun, M. and Baird, A. (1991) A dual receptor system is required for basic fibroblast growth factor activity. Cell 67, 229-231CrossRefGoogle ScholarPubMed
129Tsukamoto, A.S. et al. (1988) Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 55, 619-625CrossRefGoogle ScholarPubMed
130Welm, B.E. et al. (2002) Inducible dimerization of FGFR1: development of a mouse model to analyze progressive transformation of the mammary gland. Journal of Cell Biology 157, 703-714CrossRefGoogle ScholarPubMed
131Penault-Llorca, F. et al. (1995) Expression of FGF and FGF receptor genes in human breast cancer. International Journal of Cancer 61, 170-176CrossRefGoogle ScholarPubMed
132Zammit, C. et al. (2002) Fibroblast growth factor 8 is expressed at higher levels in lactating human breast and in breast cancer. British Journal of Cancer 86, 1097-1103CrossRefGoogle ScholarPubMed
133Tamaru, N. et al. (2004) Estrogen receptor-associated expression of keratinocyte growth factor and its possible role in the inhibition of apoptosis in human breast cancer. Laboratory Investigation 84, 1460-1471CrossRefGoogle ScholarPubMed
134Theodorou, V. et al. (2004) Fgf10 is an oncogene activated by MMTV insertional mutagenesis in mouse mammary tumors and overexpressed in a subset of human breast carcinomas. Oncogene 23, 6047-6055CrossRefGoogle Scholar
135Reis-Filho, J.S. et al. (2006) FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas. Clinical Cancer Research 12, 6652-6662CrossRefGoogle ScholarPubMed
136Meijer, D. et al. (2008) Fibroblast growth factor receptor 4 predicts failure on tamoxifen therapy in patients with recurrent breast cancer. Endocrine-Related Cancer 15, 101-111CrossRefGoogle ScholarPubMed
137Luqmani, Y.A., Graham, M. and Coombes, R.C. (1992) Expression of basic fibroblast growth factor, FGFR1 and FGFR2 in normal and malignant human breast, and comparison with other normal tissues. British Journal of Cancer 66, 273-280CrossRefGoogle ScholarPubMed
138Hunter, D.J. et al. (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nature Genetics 39, 870-874CrossRefGoogle ScholarPubMed
139Easton, D.F. et al. (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447, 1087-1093CrossRefGoogle ScholarPubMed
140Meyer, K.B. et al. (2008) Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer. PLoS Biology 6, e108CrossRefGoogle ScholarPubMed
141Kagan, B.L. et al. (2003) Complex regulation of the fibroblast growth factor-binding protein in MDA- MB-468 breast cancer cells by CCAAT/enhancer-binding protein beta. Cancer Research 63, 1696-1705Google ScholarPubMed
142Czubayko, F. et al. (1994) Tumor growth and angiogenesis induced by a secreted binding protein for fibroblast growth factors. Journal of Biological Chemistry 269, 28243-28248CrossRefGoogle ScholarPubMed
143Papa, V. et al. (1990) Elevated insulin receptor content in human breast cancer. Journal of Clinical Investigation 86, 1503-1510CrossRefGoogle ScholarPubMed
144Holdaway, I.M. and Friesen, H.G. (1977) Hormone binding by human mammary carcinoma. Cancer Research 37, 1946-1952Google ScholarPubMed
145Milazzo, G. et al. (1992) Insulin receptor expression and function in human breast cancer cell lines. Cancer Research 52, 3924-3930Google ScholarPubMed
146Finlayson, C.A. et al. (2003) Enhanced insulin signaling via Shc in human breast cancer. Metabolism 52, 1606-1611CrossRefGoogle ScholarPubMed
147Pekonen, F. et al. (1988) Receptors for epidermal growth factor and insulin-like growth factor I and their relation to steroid receptors in human breast cancer. Cancer Research 48, 1343-1347Google ScholarPubMed
148Foekens, J.A. et al. (1989) Prognostic value of receptors for insulin-like growth factor 1, somatostatin, and epidermal growth factor in human breast cancer. Cancer Research 49, 7002-7009Google ScholarPubMed
149Bonneterre, J. et al. (1990) Prognostic significance of insulin-like growth factor 1 receptors in human breast cancer. Cancer Research 50, 6931-6935Google ScholarPubMed
150Surmacz, E. (2000) Function of the IGF-I receptor in breast cancer. Journal of Mammary Gland Biology and Neoplasia 5, 95-105CrossRefGoogle ScholarPubMed
151Goodwin, P.J. et al. (2002) Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. Journal of Clinical Oncology 20, 42-51CrossRefGoogle ScholarPubMed
152Pasanisi, P. et al. (2006) Metabolic syndrome as a prognostic factor for breast cancer recurrences. International Journal of Cancer 119, 236-238CrossRefGoogle ScholarPubMed
153Pasanisi, P. et al. (2008) Serum insulin-like growth factor-I and platelet-derived growth factor as biomarkers of breast cancer prognosis. Cancer Epidemiology Biomarkers & Prevention 17, 1719-1722CrossRefGoogle ScholarPubMed
154Papa, V., Costantino, A. and Belfiore, A. (1997) Insulin receptor what role in breast cancer? Trends in Endocrinology and Metabolism 8, 306-312CrossRefGoogle ScholarPubMed
155Lu, M., Seufert, J. and Habener, J.F. (1997) Pancreatic beta-cell-specific repression of insulin gene transcription by CCAAT/enhancer-binding protein beta. Inhibitory interactions with basic helix-loop-helix transcription factor E47. Journal of Biological Chemistry 272, 28349-28359CrossRefGoogle ScholarPubMed
156Seufert, J., Weir, G.C. and Habener, J.F. (1998) Differential expression of the insulin gene transcriptional repressor CCAAT/enhancer-binding protein beta and transactivator islet duodenum homeobox-1 in rat pancreatic beta cells during the development of diabetes mellitus. Journal of Clinical Investigation 101, 2528-2539CrossRefGoogle ScholarPubMed
157Shen, C.N. et al. (2003) Glucocorticoids suppress beta-cell development and induce hepatic metaplasia in embryonic pancreas. Biochemical Journal 375, 41-50CrossRefGoogle ScholarPubMed
158Wang, L. et al. (2000) Increased insulin receptor substrate-1 and enhanced skeletal muscle insulin sensitivity in mice lacking CCAAT/enhancer-binding protein beta. Journal of Biological Chemistry 275, 14173-14181CrossRefGoogle ScholarPubMed
159Foti, D. et al. (2003) A nucleoprotein complex containing Sp1, C/EBP beta, and HMGI-Y controls human insulin receptor gene transcription. Molecular and Cellular Biology 23, 2720-2732CrossRefGoogle ScholarPubMed
160MacDougald, O.A. et al. (1995) Insulin regulates transcription of the CCAAT/enhancer binding protein (C/EBP) alpha, beta, and delta genes in fully-differentiated 3T3-L1 adipocytes. Journal of Biological Chemistry 270, 647-654CrossRefGoogle ScholarPubMed
161Le Lay, S. et al. (2002) Insulin and sterol-regulatory element-binding protein-1c (SREBP-1C) regulation of gene expression in 3T3-L1 adipocytes. Identification of CCAAT/enhancer-binding protein beta as an SREBP-1C target. Journal of Biological Chemistry 277, 35625-35634CrossRefGoogle ScholarPubMed
162Duong, D.T. et al. (2002) Insulin inhibits hepatocellular glucose production by utilizing liver-enriched transcriptional inhibitory protein to disrupt the association of CREB-binding protein and RNA polymerase II with the phosphoenolpyruvate carboxykinase gene promoter. Journal of Biological Chemistry 277, 32234-32242CrossRefGoogle ScholarPubMed
163Bosch, F., Sabater, J. and Valera, A. (1995) Insulin inhibits liver expression of the CCAAT/enhancer-binding protein beta. Diabetes 44, 267-271CrossRefGoogle ScholarPubMed
164Sekine, O. et al. (2002) Insulin activates CCAAT/enhancer binding proteins and proinflammatory gene expression through the phosphatidylinositol 3-kinase pathway in vascular smooth muscle cells. Journal of Biological Chemistry 277, 36631-36639CrossRefGoogle ScholarPubMed
165Guo, S. et al. (2001) Insulin suppresses transactivation by CAAT/enhancer-binding proteins beta (C/EBPbeta). Signaling to p300/CREB-binding protein by protein kinase B disrupts interaction with the major activation domain of C/EBPbeta. Journal of Biological Chemistry 276, 8516-8523CrossRefGoogle Scholar
166Grimm, S.L. et al. (2002) Disruption of steroid and prolactin receptor patterning in the mammary gland correlates with a block in lobuloalveolar development. Molecular Endocrinology 16, 2675-2691CrossRefGoogle ScholarPubMed
167Nolten, L.A. et al. (1994) Expression of the insulin-like growth factor I gene is stimulated by the liver-enriched transcription factors C/EBP alpha and LAP. Molecular Endocrinology 8, 1636-1645Google ScholarPubMed
168Umayahara, Y. et al. (2002) Protein kinase C-dependent, CCAAT/enhancer-binding protein beta-mediated expression of insulin-like growth factor I gene. Journal of Biological Chemistry 277, 15261-15270CrossRefGoogle ScholarPubMed
169Umayahara, Y. et al. (1999) CCAAT/enhancer-binding protein delta is a critical regulator of insulin-like growth factor-I gene transcription in osteoblasts. Journal of Biological Chemistry 274, 10609-10617CrossRefGoogle ScholarPubMed
170McCarthy, T.L. et al. (2000) Time- and dose-related interactions between glucocorticoid and cyclic adenosine 3′,5′-monophosphate on CCAAT/enhancer-binding protein-dependent insulin-like growth factor I expression by osteoblasts. Endocrinology 141, 127-137CrossRefGoogle ScholarPubMed
171Nerlov, C. (2007) The C/EBP family of transcription factors: a paradigm for interaction between gene expression and proliferation control. Trends in Cell Biology 17, 318-324CrossRefGoogle Scholar
172Brennan, P., Donev, R. and Hewamana, S. (2008) Targeting transcription factors for therapeutic benefit. Molecular Biosystems 4, 909-919CrossRefGoogle ScholarPubMed
173Minucci, S. and Pelicci, P.G. (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nature Reviews. Cancer 6, 38-51Google Scholar
174Liu, X. et al. (2008) The structural basis of protein acetylation by the p300/CBP transcriptional coactivator. Nature 451, 846-850CrossRefGoogle ScholarPubMed
175Zheng, Y. et al. (2004) Selective HAT inhibitors as mechanistic tools for protein acetylation. Methods in Enzymology 376, 188-199CrossRefGoogle ScholarPubMed
176Kohno, M. and Pouyssegur, J. (2006) Targeting the ERK signaling pathway in cancer therapy. Annals of Medicine 38, 200-211CrossRefGoogle ScholarPubMed
177Yuan, T.L. and Cantley, L.C. (2008) PI3K pathway alterations in cancer: variations on a theme. Oncogene 27, 5497-5510CrossRefGoogle ScholarPubMed
178Gilmore, T.D. and Herscovitch, M. (2006) Inhibitors of NF-kappaB signaling: 785 and counting. Oncogene 25, 6887-6899CrossRefGoogle ScholarPubMed
179Dey, A., Verma, C.S. and Lane, D.P. (2008) Updates on p53: modulation of p53 degradation as a therapeutic approach. British Journal of Cancer 98, 4-8CrossRefGoogle ScholarPubMed
180Mees, C., Nemunaitis, J. and Senzer, N. (2009) Transcription factors: their potential as targets for an individualized therapeutic approach to cancer. Cancer Gene Therapy 16, 103-112CrossRefGoogle ScholarPubMed
181Rizzo, P. et al. (2008) Rational targeting of Notch signaling in cancer. Oncogene 27, 5124-5131CrossRefGoogle ScholarPubMed
182Rishi, V. et al. (2005) A high-throughput fluorescence-anisotropy screen that identifies small molecule inhibitors of the DNA binding of B-ZIP transcription factors. Analytical Biochemistry 340, 259-271CrossRefGoogle ScholarPubMed
183Turkson, J. et al. (2001) Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation. Journal of Biological Chemistry 276, 45443-45455CrossRefGoogle ScholarPubMed
184Berg, T. et al. (2002) Small-molecule antagonists of Myc/Max dimerization inhibit Myc-induced transformation of chicken embryo fibroblasts. Proceedings of the National Academy of Sciences of the United States of America 99, 3830-3835CrossRefGoogle ScholarPubMed
185Vassilev, L.T. et al. (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844-848CrossRefGoogle ScholarPubMed
186Efeyan, A. et al. (2007) Induction of p53-dependent senescence by the MDM2 antagonist nutlin-3a in mouse cells of fibroblast origin. Cancer Research 67, 7350-7357CrossRefGoogle ScholarPubMed
187Olenyuk, B.Z. et al. (2004) Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist. Proceedings of the National Academy of Sciences of the United States of America 101, 16768-16773CrossRefGoogle ScholarPubMed
188Kozak, M. (1991) An analysis of vertebrate mRNA sequences: intimations of translational control. Journal of Cell Biology 115, 887-903CrossRefGoogle ScholarPubMed
189Raught, B. et al. (1996) Expression of a translationally regulated, dominant-negative CCAAT/enhancer-binding protein beta isoform and up-regulation of the eukaryotic translation initiation factor 2alpha are correlated with neoplastic transformation of mammary epithelial cells. Cancer Research 56, 4382-4386Google ScholarPubMed
190Lincoln, A.J. et al. (1998) Inhibition of CCAAT/enhancer-binding protein alpha and beta translation by upstream open reading frames. Journal of Biological Chemistry 273, 9552-9560CrossRefGoogle ScholarPubMed
191Li, Y. et al. (2008) Differential control of the CCAAT/enhancer-binding protein beta (C/EBPbeta) products liver-enriched transcriptional activating protein (LAP) and liver-enriched transcriptional inhibitory protein (LIP) and the regulation of gene expression during the response to endoplasmic reticulum stress. Journal of Biological Chemistry 283, 22443-22456CrossRefGoogle ScholarPubMed
192Sterneck, E., Tessarollo, L. and Johnson, P.F. (1997) An essential role for C/EBPbeta in female reproduction. Genes and Development 11, 2153-2162CrossRefGoogle ScholarPubMed
193Millward, C.A. et al. (2007) Mice with a deletion in the gene for CCAAT/enhancer-binding protein beta are protected against diet-induced obesity. Diabetes 56, 161-167CrossRefGoogle ScholarPubMed
194Carmona, M.C. et al. (2005) Defective thermoregulation, impaired lipid metabolism, but preserved adrenergic induction of gene expression in brown fat of mice lacking C/EBPbeta. Biochemistry Journal 389, 47-56CrossRefGoogle ScholarPubMed
195Croniger, C.M. et al. (2001) Mice with a deletion in the gene for CCAAT/enhancer-binding protein beta have an attenuated response to cAMP and impaired carbohydrate metabolism. Journal of Biological Chemistry 276, 629-638CrossRefGoogle ScholarPubMed
196Liu, S. et al. (1999) Hypoglycemia and impaired hepatic glucose production in mice with a deletion of the C/EBPbeta gene. Journal of Clinical Investigation 103, 207-213CrossRefGoogle ScholarPubMed
197Greenbaum, L.E. et al. (1998) CCAAT enhancer- binding protein beta is required for normal hepatocyte proliferation in mice after partial hepatectomy. Journal of Clinical Investigation 102, 996-1007CrossRefGoogle ScholarPubMed
198Tominaga, H. et al. (2008) CCAAT/Enhancer-binding Protein {beta} Promotes Osteoblast Differentiation by Enhancing Runx2 Activity with ATF4. Molecular Biology of the Cell 19, 5373-5386CrossRefGoogle ScholarPubMed
199Tanaka, T. et al. (1995) Targeted disruption of the NF-IL6 gene discloses its essential role in bacteria killing and tumor cytotoxicity by macrophages. Cell 80, 353-361CrossRefGoogle ScholarPubMed
200Screpanti, I. et al. (1995) Lymphoproliferative disorder and imbalanced T-helper response in C/EBP beta-deficient mice. EMBO Journal 14, 1932-1941CrossRefGoogle ScholarPubMed
201Tanaka, T. et al. (1997) Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. EMBO Journal 16, 7432-7443CrossRefGoogle ScholarPubMed

Further reading, resources and contacts

Information about breast cancer treatment, prevention, genetics, causes, screening, clinical trials, research and statistics from the National Cancer Institute can be found at:

White, A.W., Westwell, A.D. and Brahemi, G. (2008) Protein-protein interactions as targets for small molecule therapeutics. Expert Reviews in Molecular Medicine 10, 1-14CrossRefGoogle ScholarPubMed
White, A.W., Westwell, A.D. and Brahemi, G. (2008) Protein-protein interactions as targets for small molecule therapeutics. Expert Reviews in Molecular Medicine 10, 1-14CrossRefGoogle ScholarPubMed