Transgenic mice with lymphoid-restricted overexpression of the double bromodomain protein bromodomain-containing 2 (Brd2) develop splenic B-cell lymphoma and, upon transplantation, B-cell leukemia with leukemic infiltrates in liver and lung. Brd2 is a nuclear-localized transcription factor kinase that is most closely related to TATA box binding protein-associated factor, 250 kDa (TAF II 250) and the Drosophila developmental protein female sterile homeotic. Constitutive expression of BRD2 in the lymphoid compartment increases cyclin A transcription, "priming" transgenic B cells for proliferation. Mice stochastically develop an aggressive B-cell lymphoma with the features of B-1 cells, including CD5 and surface IgM expression. The B-cell lymphoma is monoclonal for immunoglobulin gene rearrangement and is phenotypically stable. The lymphoblasts are very large and express a transcriptome that is similar to human non-Hodgkin lymphomas. Both a wild-type BRD2 transgene and a kinase-null point mutant drive lymphomagenesis; therefore we propose that, rather than kinase activity, Brd2-mediated recruitment of E2 promoter binding factors (E2Fs) and a specific histone acetyltransferase to the cyclin A promoter by both types of transgene is a mechanistic basis for neoplasia. This report is the first to describe a transgenic mouse model for constitutive expression of a protein with more than one bromodomain. IntroductionProper transcriptional control of the cell cycle is necessary to avoid errors that can lead to neoplastic transformation. Bromodomaincontaining proteins 1-3 recently garnered attention for their roles as transcriptional regulators and their links to chromatin-modifying activities. The bromodomain motif [4][5][6] is found in proteins with intrinsic histone acetyltransferase (HAT) activity, 7-9 such as CREB (cyclic adenosine monophosphate [cAMP]-response element binding protein) binding protein (CBP), Gcn5, and TAF II 250; in protein adapters that associate with HAT-containing multiprotein complexes, such as polybromo 10 ; in certain transcription factors, 11 such as suppressor of Ty 7 (Spt7); or in chromatin remodeling machines, such as switch 2/sucrose nonfermenting 2 (Swi2/Snf2) and brahma. 12 Bromodomain proteins bind ⑀-aminoacetyl-lysines of core histones, at least in the case of p300/CBP-associated factor (p/CAF), facilitating changes in nucleosome structure. 13 The bromodomain/ extraterminal domain (BET) protein family, defined by aminoterminal bromodomains and an "extraterminal domain," 14 includes (formerly 15 RING3 [really interesting new gene 3]) and female sterile homeotic. 16 These transcriptional regulators contain 2 mutually related bromodomains that are most similar in primary sequence to the bromodomain of CBP, yet in overall structural organization most similar to TATA box binding protein-associated factor, 250 kDa (TAF II 250), which has 2 bromodomains. 14 The yeast BET protein bromodomain factor 1 (Bdf1) binds acetylated nucleosomal lysines 17,18 and combines with yeast TATA box binding prote...

Only about 5% of human breast cancers can be attributed to inheritance of breast cancer susceptibility genes, while the balance are considered to be sporadic in origin. Breast cancer incidence varies with diet and other environmental influences, including carcinogen exposure. However, the effects of environmental carcinogens on cell growth control pathways are poorly understood. Here we have examined oncogenic signaling pathways that are activated in mammary tumors in mice treated with the prototypical polycyclic aromatic hydrocarbon (PAH) 7,12-dimethylbenz[a]anthracene (DMBA). In female FVB mice given 6 doses of 1 mg of DMBA by weekly gavage beginning at 5 weeks of age, all of the mice developed tumors by 34 weeks of age (median 20 weeks after beginning DMBA); 75% of the mice had mammary tumors. DMBA-induced mammary tumors exhibited elevated expression of the aryl hydrocarbon receptor (AhR), c-myc, cyclin D1, and hyperphosphorylated retinoblastoma (Rb) protein. Because of this, the activation of upstream regulatory pathways was assessed, and elements of the Wnt signaling pathway, the NF-kappa B pathway, and the prolyl isomerase Pin-1 were found to be frequently up-regulated in the tumors when compared to normal mammary gland controls. These data suggest that environmental carcinogens can produce long-lasting alterations in growth and anti-apoptotic pathways, leading to mammary tumorigenesis.