BRD4

Summary

Gene Symbol: BRD4
Description: bromodomain containing 4
Alias: CAP, HUNK1, HUNKI, MCAP, bromodomain-containing protein 4, chromosome-associated protein
Species: human
Products:     BRD4

Top Publications

  1. Schröder S, Cho S, Zeng L, Zhang Q, Kaehlcke K, Mak L, et al. Two-pronged binding with bromodomain-containing protein 4 liberates positive transcription elongation factor b from inactive ribonucleoprotein complexes. J Biol Chem. 2012;287:1090-9 pubmed publisher
    ..inhibitory molecule HEXIM1, and an active form, part of which associates with the bromodomain-containing protein BRD4. Here, we define a novel interaction between P-TEFb and BRD4 involving tri-acetylated cyclin T1 (acK380, acK386, ..
  2. Dey A, Ellenberg J, Farina A, Coleman A, Maruyama T, Sciortino S, et al. A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transition. Mol Cell Biol. 2000;20:6537-49 pubmed
    We describe a novel nuclear factor called mitotic chromosome-associated protein (MCAP), which belongs to the poorly understood BET subgroup of the bromodomain superfamily...
  3. Devaiah B, Lewis B, Cherman N, Hewitt M, Albrecht B, Robey P, et al. BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain. Proc Natl Acad Sci U S A. 2012;109:6927-32 pubmed publisher
    The bromodomain protein, BRD4, has been identified recently as a therapeutic target in acute myeloid leukemia, multiple myeloma, Burkitt's lymphoma, NUT midline carcinoma, colon cancer, and inflammatory disease; its loss is a prognostic ..
  4. Bisgrove D, Mahmoudi T, Henklein P, Verdin E. Conserved P-TEFb-interacting domain of BRD4 inhibits HIV transcription. Proc Natl Acad Sci U S A. 2007;104:13690-5 pubmed
    We have identified a conserved region in the C-terminal domain of bromodomain-containing protein 4 (BRD4) that mediates its specific interaction with positive transcription elongation factor b (P-TEFb)...
  5. Di Micco R, Fontanals Cirera B, Low V, Ntziachristos P, Yuen S, Lovell C, et al. Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes. Cell Rep. 2014;9:234-47 pubmed publisher
    ..Here, we demonstrate that BRD4, a member of the bromodomain and extraterminal domain (BET) family of epigenetic readers, regulates the self-..
  6. Yang Z, Yik J, Chen R, He N, Jang M, Ozato K, et al. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell. 2005;19:535-45 pubmed
    ..Here, we show that the remaining half associates with the bromodomain protein Brd4. In stress-induced cells, the 7SK/HEXIM1-bound P-TEFb is quantitatively converted into the Brd4-associated form...
  7. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith W, Fedorov O, et al. Selective inhibition of BET bromodomains. Nature. 2010;468:1067-73 pubmed publisher
    ..of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity...
  8. French C, Ramirez C, Kolmakova J, Hickman T, Cameron M, Thyne M, et al. BRD-NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells. Oncogene. 2008;27:2237-42 pubmed
    ..In about 2/3rds of cases, NUT is fused to BRD4 on chromosome 19...
  9. Muller M, Jacob Y, Jones L, Weiss A, Brino L, Chantier T, et al. Large scale genotype comparison of human papillomavirus E2-host interaction networks provides new insights for e2 molecular functions. PLoS Pathog. 2012;8:e1002761 pubmed publisher
    ..These include transcription regulation, regulation of apoptosis, RNA processing, ubiquitination and intracellular trafficking. The present work provides an overview of E2 biological functions across multiple HPV genotypes. ..

More Information

Publications62

  1. Boehm D, Calvanese V, Dar R, Xing S, Schroeder S, Martins L, et al. BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism. Cell Cycle. 2013;12:452-62 pubmed publisher
    ..p-TEFb but independent from the viral Tat protein, arguing against the possibility that removal of the BET protein BRD4, which functions as a cellular competitor for Tat, serves as a primary mechanism for BET inhibitor action...
  2. Gagnon D, Joubert S, Sénéchal H, Fradet Turcotte A, Torre S, Archambault J. Proteasomal degradation of the papillomavirus E2 protein is inhibited by overexpression of bromodomain-containing protein 4. J Virol. 2009;83:4127-39 pubmed publisher
    ..transactivation domain, the region that binds to the cellular chromatin factor bromodomain-containing protein 4 (Brd4) to regulate viral gene transcription...
  3. Farina A, Hattori M, Qin J, Nakatani Y, Minato N, Ozato K. Bromodomain protein Brd4 binds to GTPase-activating SPA-1, modulating its activity and subcellular localization. Mol Cell Biol. 2004;24:9059-69 pubmed
    b>Brd4 is a mammalian protein that contains a double bromodomain. It binds to chromatin and regulates cell cycle progression at multiple stages...
  4. Wang R, Li Q, Helfer C, Jiao J, You J. Bromodomain protein Brd4 associated with acetylated chromatin is important for maintenance of higher-order chromatin structure. J Biol Chem. 2012;287:10738-52 pubmed publisher
    ..In this study, we demonstrate that Brd4 (bromodomain-containing protein 4) protein participates in the maintenance of the higher-order chromatin structure...
  5. French C, Miyoshi I, Kubonishi I, Grier H, Perez Atayde A, Fletcher J. BRD4-NUT fusion oncogene: a novel mechanism in aggressive carcinoma. Cancer Res. 2003;63:304-7 pubmed
    ..The chromosome 19 translocation breakpoint targets the BRD4 double bromodomain-containing gene, which functions in regulation of cell cycle progression...
  6. Floyd S, Pacold M, Huang Q, Clarke S, Lam F, Cannell I, et al. The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. Nature. 2013;498:246-50 pubmed publisher
    ..We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response ..
  7. Zhang G, Liu R, Zhong Y, Plotnikov A, Zhang W, Zeng L, et al. Down-regulation of NF-κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition. J Biol Chem. 2012;287:28840-51 pubmed publisher
    ..of NF-κB transcriptional activity by small molecule blocking NF-κB binding to the transcriptional cofactor BRD4, which is required for the assembly of the productive transcriptional complex comprising positive transcription ..
  8. Weidner Glunde M, Ottinger M, Schulz T. WHAT do viruses BET on?. Front Biosci (Landmark Ed). 2010;15:537-49 pubmed
    ..The two most studied BET proteins Brd2 and Brd4 have been shown to bind to viral proteins of herpesviruses and papillomaviruses...
  9. Yan J, Li Q, Lievens S, Tavernier J, You J. Abrogation of the Brd4-positive transcription elongation factor B complex by papillomavirus E2 protein contributes to viral oncogene repression. J Virol. 2010;84:76-87 pubmed publisher
    The cellular bromodomain protein Brd4 is a major interacting partner of the papillomavirus (PV) E2 protein. Interaction of E2 with Brd4 contributes to viral episome maintenance...
  10. Rahman S, Sowa M, Ottinger M, Smith J, Shi Y, Harper J, et al. The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Mol Cell Biol. 2011;31:2641-52 pubmed publisher
    Bromodomain protein 4 (Brd4) plays critical roles in development, cancer progression, and virus-host pathogenesis...
  11. Lu H, Li Z, Xue Y, Schulze Gahmen U, Johnson J, Krogan N, et al. AFF1 is a ubiquitous P-TEFb partner to enable Tat extraction of P-TEFb from 7SK snRNP and formation of SECs for HIV transactivation. Proc Natl Acad Sci U S A. 2014;111:E15-24 pubmed publisher
    ..ribonucleoprotein particle (7SK snRNP), the super elongation complexes (SECs), and the bromodomain protein 4 (Brd4)-P-TEFb complex] that constitute a P-TEFb network controlling cellular and HIV transcription...
  12. You J, Srinivasan V, Denis G, Harrington W, Ballestas M, Kaye K, et al. Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes. J Virol. 2006;80:8909-19 pubmed
    ..Because previous studies had identified bromodomain protein Brd4 as the mitotic chromosome anchor for the bovine papillomavirus E2 protein, which tethers the viral episomes to host ..
  13. Dawson M, Prinjha R, Dittmann A, Giotopoulos G, Bantscheff M, Chan W, et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011;478:529-33 pubmed publisher
    ..These findings establish the displacement of BET proteins from chromatin as a promising epigenetic therapy for these aggressive leukaemias. ..
  14. Wu S, Lee A, Lai H, Zhang H, Chiang C. Phospho switch triggers Brd4 chromatin binding and activator recruitment for gene-specific targeting. Mol Cell. 2013;49:843-57 pubmed publisher
    Bromodomain-containing protein 4 (Brd4) is an epigenetic reader and transcriptional regulator recently identified as a cancer therapeutic target for acute myeloid leukemia, multiple myeloma, and Burkitt's lymphoma...
  15. Zheng G, Schweiger M, Martinez Noel G, Zheng L, Smith J, Harper J, et al. Brd4 regulation of papillomavirus protein E2 stability. J Virol. 2009;83:8683-92 pubmed publisher
    ..Our laboratory has previously identified the cellular bromodomain protein Brd4 as a key interacting partner of E2...
  16. Baxter M, McPhillips M, Ozato K, McBride A. The mitotic chromosome binding activity of the papillomavirus E2 protein correlates with interaction with the cellular chromosomal protein, Brd4. J Virol. 2005;79:4806-18 pubmed publisher
    ..binding activity was found to correlate well with the ability to interact with the cellular chromosomal associated factor Brd4, which has recently been proposed to mediate the association between BPV1 E2 and mitotic chromosomes.
  17. Olejnik Schmidt A, Schmidt M, Kedzia W, Gozdzicka Jozefiak A. Search for cellular partners of human papillomavirus type 16 E2 protein. Arch Virol. 2008;153:983-90 pubmed publisher
    ..Using a yeast two-hybrid system, we have identified epithelial cellular proteins that bind to the E2 protein of HPV16. ..
  18. Itzen F, Greifenberg A, B sken C, Geyer M. Brd4 activates P-TEFb for RNA polymerase II CTD phosphorylation. Nucleic Acids Res. 2014;42:7577-90 pubmed publisher
    The bromodomain protein Brd4 regulates the transcription of signal-inducible genes. This is achieved by recruiting the positive transcription elongation factor P-TEFb to promoters by its P-TEFb interaction domain (PID)...
  19. Devaiah B, Singer D. Cross-talk among RNA polymerase II kinases modulates C-terminal domain phosphorylation. J Biol Chem. 2012;287:38755-66 pubmed publisher
    ..We report that three CTD kinases, CDK7, CDK9, and BRD4, engage in cross-talk, modulating their subsequent CTD phosphorylation...
  20. Dey A, Chitsaz F, Abbasi A, Misteli T, Ozato K. The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc Natl Acad Sci U S A. 2003;100:8758-63 pubmed
    ..b>Brd4 is a member of the BET family that carries two bromodomains...
  21. Parish J, Bean A, Park R, Androphy E. ChlR1 is required for loading papillomavirus E2 onto mitotic chromosomes and viral genome maintenance. Mol Cell. 2006;24:867-76 pubmed
    ..Viral genomes encoding this E2 mutation are not episomally maintained in cell culture. Notably, E2 W130R binds Brd4, which reportedly acts as a mitotic tether, indicating this interaction is insufficient for E2 association with ..
  22. Jang M, Shen K, McBride A. Papillomavirus genomes associate with BRD4 to replicate at fragile sites in the host genome. PLoS Pathog. 2014;10:e1004117 pubmed publisher
    ..The papillomavirus E2 protein, in complex with BRD4, tethers the viral genome to host chromatin to ensure persistent replication...
  23. Rodriguez R, Huidobro C, Urdinguio R, Mangas C, Soldevilla B, Dominguez G, et al. Aberrant epigenetic regulation of bromodomain BRD4 in human colon cancer. J Mol Med (Berl). 2012;90:587-95 pubmed publisher
    The bromodomain protein BRD4 is involved in cell proliferation and cell cycle progression, primarily through its role in acetylated chromatin-dependent regulation of transcription at targeted loci...
  24. Schweiger M, Ottinger M, You J, Howley P. Brd4-independent transcriptional repression function of the papillomavirus e2 proteins. J Virol. 2007;81:9612-22 pubmed
    ..We have previously identified the cellular bromodomain protein Brd4 as a major E2-interacting protein and established that it participates in tethering bovine papillomavirus type 1 E2 ..
  25. Sénéchal H, Poirier G, Coulombe B, Laimins L, Archambault J. Amino acid substitutions that specifically impair the transcriptional activity of papillomavirus E2 affect binding to the long isoform of Brd4. Virology. 2007;358:10-7 pubmed
    ..The major TAD-binding protein was identified by mass spectrometry and western blotting as the long isoform of Brd4. Binding to Brd4 was also demonstrated for the E2 TADs of other papillomaviruses including cutaneous and animal ..
  26. Zhang W, Prakash C, Sum C, Gong Y, Li Y, Kwok J, et al. Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012;287:43137-55 pubmed publisher
    ..by positive transcription elongation factor b (P-TEFb) in association with bromodomain-containing protein 4 (BRD4)...
  27. French C, Miyoshi I, Aster J, Kubonishi I, Kroll T, Dal Cin P, et al. BRD4 bromodomain gene rearrangement in aggressive carcinoma with translocation t(15;19). Am J Pathol. 2001;159:1987-92 pubmed
    ..mechanism in which the chromosome 19 translocation breakpoint interrupts the coding sequence of a bromodomain gene, BRD4. These studies implicate BRD4 as a potential partner in a t(15;19)-associated fusion oncogene...
  28. Abbate E, Voitenleitner C, Botchan M. Structure of the papillomavirus DNA-tethering complex E2:Brd4 and a peptide that ablates HPV chromosomal association. Mol Cell. 2006;24:877-89 pubmed
    ..The chromosomal protein Brd4 is implicated in the hitchhiking of bovine papillomavirus-1 (BPV-1), and the viral protein E2 binds to both ..
  29. Schweiger M, You J, Howley P. Bromodomain protein 4 mediates the papillomavirus E2 transcriptional activation function. J Virol. 2006;80:4276-85 pubmed
    ..b>Brd4 has recently been identified as a major E2-interacting protein and, in the case of the bovine papillomavirus type 1,..
  30. Yang Z, He N, Zhou Q. Brd4 recruits P-TEFb to chromosomes at late mitosis to promote G1 gene expression and cell cycle progression. Mol Cell Biol. 2008;28:967-76 pubmed
    b>Brd4, a bromodomain protein capable of interacting with acetylated histones, is implicated in transmitting epigenetic memory through mitosis...
  31. Bandopadhayay P, Bergthold G, Nguyen B, Schubert S, Gholamin S, Tang Y, et al. BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin Cancer Res. 2014;20:912-25 pubmed publisher
    ..The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma...
  32. Liu Y, Wang X, Zhang J, Huang H, Ding B, Wu J, et al. Structural basis and binding properties of the second bromodomain of Brd4 with acetylated histone tails. Biochemistry. 2008;47:6403-17 pubmed publisher
    b>Brd4 belongs to the BET family. It is a multifunctional protein involved in transcription, replication, the signal transduction pathway, and cell cycle progression...
  33. You J, Croyle J, Nishimura A, Ozato K, Howley P. Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes. Cell. 2004;117:349-60 pubmed
    ..We have identified the bromodomain protein Brd4 as a major cellular interacting partner of the bovine papillomavirus E2...
  34. Dow E, Liu H, Rice A. T-loop phosphorylated Cdk9 localizes to nuclear speckle domains which may serve as sites of active P-TEFb function and exchange between the Brd4 and 7SK/HEXIM1 regulatory complexes. J Cell Physiol. 2010;224:84-93 pubmed publisher
    ..Lastly, both the Brd4 and HEXIM1 proteins interact with P-TEFb at or very near speckle domains and treatment of cells with the Cdk9 ..
  35. Maruyama T, Farina A, Dey A, Cheong J, Bermudez V, Tamura T, et al. A Mammalian bromodomain protein, brd4, interacts with replication factor C and inhibits progression to S phase. Mol Cell Biol. 2002;22:6509-20 pubmed
    b>Brd4 belongs to the BET family of nuclear proteins that carry two bromodomains implicated in the interaction with chromatin. Expression of Brd4 correlates with cell growth and is induced during early G(1) upon mitogenic stimuli...
  36. He N, Pezda A, Zhou Q. Modulation of a P-TEFb functional equilibrium for the global control of cell growth and differentiation. Mol Cell Biol. 2006;26:7068-76 pubmed
    ..It is kept in a functional equilibrium through alternately interacting with its positive (the Brd4 protein) and negative (the HEXIM1 protein and 7SK snRNA) regulators...
  37. You J, Li Q, Wu C, Kim J, Ottinger M, Howley P. Regulation of aurora B expression by the bromodomain protein Brd4. Mol Cell Biol. 2009;29:5094-103 pubmed publisher
    The bromodomain protein Brd4 plays critical roles in cellular proliferation and cell cycle progression...
  38. Li Z, Guo J, Wu Y, Zhou Q. The BET bromodomain inhibitor JQ1 activates HIV latency through antagonizing Brd4 inhibition of Tat-transactivation. Nucleic Acids Res. 2013;41:277-87 pubmed publisher
    ..Here, we identify the bromodomain protein Brd4 and its inhibition of Tat-transactivation as a major impediment to latency reactivation...
  39. Wang X, Li J, Schowalter R, Jiao J, Buck C, You J. Bromodomain protein Brd4 plays a key role in Merkel cell polyomavirus DNA replication. PLoS Pathog. 2012;8:e1003021 pubmed publisher
    ..In this study, we demonstrate that bromodomain protein 4 (Brd4) interacts with MCV large T antigen (LT) and plays a critical role in viral DNA replication...
  40. McBride A, Jang M. Current understanding of the role of the Brd4 protein in the papillomavirus lifecycle. Viruses. 2013;5:1374-94 pubmed publisher
    The Brd4 protein is an epigenetic reader that is central to regulation of cellular transcription and mitotic bookmarking. The transcription and replication proteins of many viruses interact with Brd4...
  41. Jang M, Kwon D, McBride A. Papillomavirus E2 proteins and the host BRD4 protein associate with transcriptionally active cellular chromatin. J Virol. 2009;83:2592-600 pubmed publisher
    The interaction of papillomavirus E2 proteins with cellular Brd4 protein is important for transcriptional regulation of viral genes and partitioning of viral genomes...
  42. Huang B, Yang X, Zhou M, Ozato K, Chen L. Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA. Mol Cell Biol. 2009;29:1375-87 pubmed publisher
    ..In this study, we demonstrate that bromodomains of Brd4 bind to acetylated lysine-310...
  43. Zhu J, Gaiha G, John S, Pertel T, Chin C, Gao G, et al. Reactivation of latent HIV-1 by inhibition of BRD4. Cell Rep. 2012;2:807-16 pubmed publisher
    ..Using orthologous genetic screens, we identified bromodomain containing 4 (BRD4) as a negative regulator of HIV-1 replication...
  44. Wu S, Lee A, Hou S, Kemper J, Erdjument Bromage H, Tempst P, et al. Brd4 links chromatin targeting to HPV transcriptional silencing. Genes Dev. 2006;20:2383-96 pubmed
    ..Surprisingly, the double bromodomain-containing protein Brd4, which is implicated in cell cycle control and viral genome segregation, was found associated with E2 and conferred ..
  45. Lee A, Chiang C. Chromatin adaptor Brd4 modulates E2 transcription activity and protein stability. J Biol Chem. 2009;284:2778-86 pubmed publisher
    b>Brd4 is a chromatin adaptor containing tandem bromodomains binding to acetylated histone H3 and H4...
  46. Wang X, Helfer C, Pancholi N, Bradner J, You J. Recruitment of Brd4 to the human papillomavirus type 16 DNA replication complex is essential for replication of viral DNA. J Virol. 2013;87:3871-84 pubmed publisher
    ..Bromodomain-containing protein 4 (Brd4) interacts with viral E2 protein to mediate papillomavirus (PV) genome maintenance and viral transcription...
  47. Yan J, Diaz J, Jiao J, Wang R, You J. Perturbation of BRD4 protein function by BRD4-NUT protein abrogates cellular differentiation in NUT midline carcinoma. J Biol Chem. 2011;286:27663-75 pubmed publisher
    ..fusion of the NUT (nuclear protein in testis) gene on chromosome 15 to a few other genes, most frequently the BRD4 gene on chromosome 19...
  48. Sakakibara N, Chen D, Jang M, Kang D, Luecke H, Wu S, et al. Brd4 is displaced from HPV replication factories as they expand and amplify viral DNA. PLoS Pathog. 2013;9:e1003777 pubmed publisher
    ..We show that the Brd4 protein localizes to these foci and is essential for their formation...
  49. Reynoird N, Schwartz B, Delvecchio M, Sadoul K, Meyers D, Mukherjee C, et al. Oncogenesis by sequestration of CBP/p300 in transcriptionally inactive hyperacetylated chromatin domains. EMBO J. 2010;29:2943-52 pubmed publisher
    ..a chromosomal translocation, t(15;19)(q13;p13), results in an in-frame fusion of the double bromodomain protein, BRD4, with a testis-specific protein of unknown function, NUT (nuclear protein in testis)...
  50. Takada T, Suzuki H, Sugiyama Y. Characterization of 5'-flanking region of human MRP3. Biochem Biophys Res Commun. 2000;270:728-32 pubmed
    ..In the present study, we investigated the mechanism for the expression of human MRP3. The cap site hunting method revealed that the transcription starts at -25 and -27 nt upstream of the initiation codon...
  51. Kabumoto K, Takatori F, Inoue M. A novel mainstream capnometer system for endoscopy delivering oxygen. Conf Proc IEEE Eng Med Biol Soc. 2017;2017:3433-3436 pubmed publisher
    ..However, oxygen administration can interfere with CO2 measurement owing to oxygen flow. Therefore, we developed cap-ONE Biteblock for patients undergoing endoscopy with oxygen supply to measure CO2 accurately...
  52. Lee J, Seo H, Im K, Park S, Kim S, Lee E, et al. Idiopathic hypereosinophilia is clonal disorder? Clonality identified by targeted sequencing. PLoS ONE. 2017;12:e0185602 pubmed publisher
    ..7%), SCRIB and STAG2 (16.7%), and SH2B3 (13.3%). Network analysis revealed that our 21 candidate genes (BIRC3, BRD4, CSF3R, DNMT3A, EGR2, EZH2, FAT4, FLT3, GATA2, IKZF, JAK2, MAPK1, MPL, NF1, NOTCH1, PTEN, RB1, RUNX1, TET2, TP53 ..
  53. Shi J, Cao J, Zhou B. Twist-BRD4 complex: potential drug target for basal-like breast cancer. Curr Pharm Des. 2015;21:1256-61 pubmed
    ..The di-acetylated Twist recruits BRD4 and related transcriptional components to super-enhancer of its targeted genes during progression of basal-like ..