Top

Published in:

10-11-2023 | REVIEW

From modulation of cellular plasticity to potentiation of therapeutic resistance: new and emerging roles of MYB transcription factors in human malignancies

Authors: Shashi Anand, Kunwar Somesh Vikramdeo, Sarabjeet Kour Sudan, Amod Sharma, Srijan Acharya, Mohammad Aslam Khan, Seema Singh, Ajay Pratap Singh

Published in: Cancer and Metastasis Reviews | Issue 1/2024

Abstract

MYB transcription factors are encoded by a large family of highly conserved genes from plants to vertebrates. There are three members of the MYB gene family in human, namely, MYB, MYBL1, and MYBL2 that encode MYB/c-MYB, MYBL1/A-MYB, and MYBL2/B-MYB, respectively. MYB was the first member to be identified as a cellular homolog of the v-myb oncogene carried by the avian myeloblastosis virus (AMV) causing leukemia in chickens. Under the normal scenario, MYB is predominantly expressed in hematopoietic tissues, colonic crypts, and neural stem cells and plays a role in maintaining the undifferentiated state of the cells. Over the years, aberrant expression of MYB genes has been reported in several malignancies and recent years have witnessed tremendous progress in understanding of their roles in processes associated with cancer development. Here, we review various MYB alterations reported in cancer along with the roles of MYB family proteins in tumor cell plasticity, therapy resistance, and other hallmarks of cancer. We also discuss studies that provide mechanistic insights into the oncogenic functions of MYB transcription factors to identify potential therapeutic vulnerabilities.

Davidson, C. J., Tirouvanziam, R., Herzenberg, L. A., & Lipsick, J. S. (2005). Functional evolution of the vertebrate Myb gene family: B-Myb, but neither A-Myb nor c-Myb, complements Drosophila Myb in hemocytes. Genetics, 169, 215–229. https://doi.org/10.1534/genetics.104.034132CrossRefPubMedPubMedCentral

Ciciro, Y., & Sala, A. (2021). MYB oncoproteins: emerging players and potential therapeutic targets in human cancer. Oncogenesis, 10, 19. https://doi.org/10.1038/s41389-021-00309-yCrossRefPubMedPubMedCentral

Klempnauer, K. H., Gonda, T. J., & Bishop, J. M. (1982). Nucleotide sequence of the retroviral leukemia gene v-myb and its cellular progenitor c-myb: The architecture of a transduced oncogene. Cell, 31, 453–463. https://doi.org/10.1016/0092-8674(82)90138-6CrossRefPubMed

Boyle, W. J., Lipsick, J. S., Reddy, E. P., & Baluda, M. A. (1983). Identification of the leukemogenic protein of avian myeloblastosis virus and of its normal cellular homologue. Proceedings of the National Academy of Science U S A, 80, 2834–2838. https://doi.org/10.1073/pnas.80.10.2834CrossRef

Oh, I. H., & Reddy, E. P. (1999). The myb gene family in cell growth, differentiation and apoptosis. Oncogene, 18, 3017–33. https://doi.org/10.1038/sj.onc.1202839CrossRefPubMed

Nomura, N., Takahashi, M., Matsui, M., Ishii, S., Date, T., Sasamoto, S., et al. (1988). Isolation of human cDNA clones of myb-related genes, A-myb and B-myb. Nucleic Acids Research, 16, 11075–11089. https://doi.org/10.1093/nar/16.23.11075CrossRefPubMedPubMedCentral

Ramsay, R. G., & Gonda, T. J. (2008). MYB function in normal and cancer cells. Nature Reviews Cancer, 8, 523–534. https://doi.org/10.1038/nrc2439CrossRefPubMed

Trauth, K., Mutschler, B., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., & Klempnauer, K. H. (1994). Mouse A-myb encodes a trans-activator and is expressed in mitotically active cells of the developing central nervous system, adult testis and B lymphocytes. The EMBO Journal, 13, 5994–6005. https://doi.org/10.1002/j.1460-2075.1994.tb06945.xCrossRefPubMedPubMedCentral

Kumar, A., Baker, S. J., Lee, C. M., & Reddy, E. P. (2003). Molecular mechanisms associated with the regulation of apoptosis by the two alternatively spliced products of c-Myb. Molecular and Cellular Biology, 23, 6631–45. https://doi.org/10.1128/MCB.23.18.6631-6645.2003CrossRefPubMedPubMedCentral

10.

Brayer, K. J., Frerich, C. A., Kang, H., & Ness, S. A. (2016). Recurrent fusions in MYB and MYBL1 define a common, transcription factor-driven oncogenic pathway in salivary gland adenoid cystic carcinoma. Cancer Discovery, 6, 176–187. https://doi.org/10.1158/2159-8290.CD-15-0859CrossRefPubMed

11.

Chen, X., Feng, J., Zhang, Y., Liu, J., Zhang, L., Zeng, P., et al. (2023). MYBL2 alternative splicing-related genetic variants reduce the risk of triple-negative breast cancer in the Chinese population. Frontiers in Genetics, 14, 1150976. https://doi.org/10.3389/fgene.2023.1150976CrossRefPubMedPubMedCentral

12.

O’Rourke, J. P., & Ness, S. A. (2008). Alternative RNA splicing produces multiple forms of c-Myb with unique transcriptional activities. Molecular and Cellular Biology, 28, 2091–2101. https://doi.org/10.1128/MCB.01870-07CrossRefPubMedPubMedCentral

13.

Ogata, K., Kanei-Ishii, C., Sasaki, M., Hatanaka, H., Nagadoi, A., Enari, M., et al. (1996). The cavity in the hydrophobic core of Myb DNA-binding domain is reserved for DNA recognition and trans-activation. Natural Structural Biology, 3, 178–187. https://doi.org/10.1038/nsb0296-178CrossRef

14.

Ogata, K., Hojo, H., Aimoto, S., Nakai, T., Nakamura, H., Sarai, A., et al. (1992). Solution structure of a DNA-binding unit of Myb: A helix-turn-helix-related motif with conserved tryptophans forming a hydrophobic core. Proceedings of the National Academy of Sciences U S A, 89, 6428–6432. https://doi.org/10.1073/pnas.89.14.6428CrossRef

15.

Facchinetti, V., Loffarelli, L., Schreek, S., Oelgeschlager, M., Luscher, B., Introna, M., et al. (1997). Regulatory domains of the A-Myb transcription factor and its interaction with the CBP/p300 adaptor molecules. Biochemical Journal, 324(Pt 3), 729–36. https://doi.org/10.1042/bj3240729CrossRefPubMedPubMedCentral

16.

Rushton, J. J., & Ness, S. A. (2001). The conserved DNA binding domain mediates similar regulatory interactions for A-Myb, B-Myb, and c-Myb transcription factors. Blood Cells, Molecules, and Diseases, 27, 459–63. https://doi.org/10.1006/bcmd.2001.0405CrossRefPubMed

17.

Ogata, K., Morikawa, S., Nakamura, H., Sekikawa, A., Inoue, T., Kanai, H., et al. (1994). Solution structure of a specific DNA complex of the Myb DNA-binding domain with cooperative recognition helices. Cell, 79, 639–648. https://doi.org/10.1016/0092-8674(94)90549-5CrossRefPubMed

18.

Bergholtz, S., Andersen, T. O., Andersson, K. B., Borrebaek, J., Luscher, B., & Gabrielsen, O. S. (2001). The highly conserved DNA-binding domains of A-, B- and c-Myb differ with respect to DNA-binding, phosphorylation and redox properties. Nucleic Acids Research, 29, 3546–3556. https://doi.org/10.1093/nar/29.17.3546CrossRefPubMedPubMedCentral

19.

Nakagoshi, H., Takemoto, Y., & Ishii, S. (1993). Functional domains of the human B-myb gene product. Journal of Biological Chemistry, 268, 14161–14167. https://doi.org/10.1016/S0021-9258(19)85222-5CrossRefPubMed

20.

Sleeman, J. P. (1993). Xenopus A-myb is expressed during early spermatogenesis. Oncogene, 8, 1931–1941.PubMed

21.

Katzen, A. L., Kornberg, T. B., & Bishop, J. M. (1985). Isolation of the proto-oncogene c-myb from D. melanogaster. Cell, 41, 449–456. https://doi.org/10.1016/S0092-8674(85)80018-0CrossRefPubMed

22.

Kanei-Ishii, C., MacMillan, E. M., Nomura, T., Sarai, A., Ramsay, R. G., Aimoto, S., et al. (1992). Transactivation and transformation by Myb are negatively regulated by a leucine-zipper structure. Proceedings National Academy Sciences U S A, 89, 3088–3092. https://doi.org/10.1073/pnas.89.7.3088CrossRef

23.

Nomura, T., Sakai, N., Sarai, A., Sudo, T., Kanei-Ishii, C., Ramsay, R. G., et al. (1993). Negative autoregulation of c-Myb activity by homodimer formation through the leucine zipper. Journal of Biological Chemistry, 268, 21914–21923. https://doi.org/10.1016/S0021-9258(20)80628-0CrossRefPubMed

24.

Takahashi, T., Nakagoshi, H., Sarai, A., Nomura, N., Yamamoto, T., & Ishii, S. (1995). Human A-myb gene encodes a transcriptional activator containing the negative regulatory domains. FEBS Letters, 358, 89–96. https://doi.org/10.1016/0014-5793(94)01402-MCrossRefPubMed

25.

Ziebold, U., & Klempnauer, K. H. (1997). Linking Myb to the cell cycle: Cyclin-dependent phosphorylation and regulation of A-Myb activity. Oncogene, 15, 1011–1019. https://doi.org/10.1038/sj.onc.1201282CrossRefPubMed

26.

Ramsay, R. G., Morrice, N., Van Eeden, P., Kanagasundaram, V., Nomura, T., De Blaquiere, J., et al. (1995). Regulation of c-Myb through protein phosphorylation and leucine zipper interactions. Oncogene, 11, 2113–2120.PubMed

27.

Wijeratne, T. U., Guiley, K. Z., Lee, H. W., Muller, G. A., & Rubin, S. M. (2022). Cyclin-dependent kinase-mediated phosphorylation and the negative regulatory domain of transcription factor B-Myb modulate its DNA binding. Journal of Biological Chemistry, 298, 102319. https://doi.org/10.1016/j.jbc.2022.102319CrossRefPubMedPubMedCentral

28.

Tomita, A., Watanabe, T., Kosugi, H., Ohashi, H., Uchida, T., Kinoshita, T., et al. (1998). Truncated c-Myb expression in the human leukemia cell line TK-6. Leukemia, 12, 1422–1429. https://doi.org/10.1038/sj.leu.2401113CrossRefPubMed

29.

Wallrapp, C., Muller-Pillasch, F., Solinas-Toldo, S., Lichter, P., Friess, H., Buchler, M., et al. (1997). Characterization of a high copy number amplification at 6q24 in pancreatic cancer identifies c-myb as a candidate oncogene. Cancer Research, 57, 3135–3139.PubMed

30.

Kauraniemi, P., Hedenfalk, I., Persson, K., Duggan, D. J., Tanner, M., Johannsson, O., et al. (2000). MYB oncogene amplification in hereditary BRCA1 breast cancer. Cancer Research, 60, 5323–5328.PubMed

31.

Tatevossian, R. G., Tang, B., Dalton, J., Forshew, T., Lawson, A. R., Ma, J., et al. (2010). MYB upregulation and genetic aberrations in a subset of pediatric low-grade gliomas. Acta Neuropathologica, 120, 731–743. https://doi.org/10.1007/s00401-010-0763-1CrossRefPubMedPubMedCentral

32.

Schumacher, S. E., Shim, B. Y., Corso, G., Ryu, M. H., Kang, Y. K., Roviello, F., et al. (2017). Somatic copy number alterations in gastric adenocarcinomas among Asian and Western patients. PLoS ONE, 12, e0176045. https://doi.org/10.1371/journal.pone.0176045CrossRefPubMedPubMedCentral

33.

Edwards, J., Krishna, N. S., Witton, C. J., & Bartlett, J. M. (2003). Gene amplifications associated with the development of hormone-resistant prostate cancer. Clinical Cancer Research, 9, 5271–5281.PubMed

34.

Dong, G., Mao, Q., Yu, D., Zhang, Y., Qiu, M., Dong, G., et al. (2017). Integrative analysis of copy number and transcriptional expression profiles in esophageal cancer to identify a novel driver gene for therapy. Sciences Reports, 7, 42060. https://doi.org/10.1038/srep42060CrossRef

35.

Ramkissoon, L. A., Horowitz, P. M., Craig, J. M., Ramkissoon, S. H., Rich, B. E., Schumacher, S. E., et al. (2013). Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proceedings National Academy Sciences U S A, 110, 8188–8193. https://doi.org/10.1073/pnas.130025211CrossRef

36.

Bayley, R., Ward, C., & Garcia, P. (2020). MYBL2 amplification in breast cancer: Molecular mechanisms and therapeutic potential. Biochimica et Biophysica Acta - Reviews on Cancer, 1874, 188407. https://doi.org/10.1016/j.bbcan.2020.188407CrossRefPubMed

37.

Koynova, D. K., Jordanova, E. S., Milev, A. D., Dijkman, R., Kirov, K. S., Toncheva, D. I., et al. (2007). Gene-specific fluorescence in-situ hybridization analysis on tissue microarray to refine the region of chromosome 20q amplification in melanoma. Melanoma Research, 17, 37–41. https://doi.org/10.1097/CMR.0b013e3280141617CrossRefPubMed

38.

Tanner, M. M., Grenman, S., Koul, A., Johannsson, O., Meltzer, P., Pejovic, T., et al. (2000). Frequent amplification of chromosomal region 20q12-q13 in ovarian cancer. Clinical Cancer Research, 6, 1833–1839.PubMed

39.

Shi, H., Bevier, M., Johansson, R., Grzybowska, E., Chen, B., Eyfjord, J. E., et al. (2011). Single nucleotide polymorphisms in the 20q13 amplicon genes in relation to breast cancer risk and clinical outcome. Breast Cancer Research and Treatment, 130, 905–916. https://doi.org/10.1007/s10549-011-1600-5CrossRefPubMed

40.

Lim, S. W., Tan, K. J., Azuraidi, O. M., Sathiya, M., Lim, E. C., Lai, K. S., et al. (2021). Functional and structural analysis of non-synonymous single nucleotide polymorphisms (nsSNPs) in the MYB oncoproteins associated with human cancer. Scientific Reports, 11, 24206. https://doi.org/10.1038/s41598-021-03624-xCrossRefPubMedPubMedCentral

41.

Stenman, G., Andersson, M. K., & Andren, Y. (2010). New tricks from an old oncogene: Gene fusion and copy number alterations of MYB in human cancer. Cell Cycle, 9, 2986–2995. https://doi.org/10.4161/cc.9.15.12515CrossRefPubMedPubMedCentral

42.

Persson, M., Andren, Y., Mark, J., Horlings, H. M., Persson, F., & Stenman, G. (2009). Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck. Proceedings National Academy Science U S A, 106, 18740–18744. https://doi.org/10.1073/pnas.0909114106CrossRef

43.

Mitani, Y., Li, J., Rao, P. H., Zhao, Y. J., Bell, D., Lippman, S. M., et al. (2010). Comprehensive analysis of the MYB-NFIB gene fusion in salivary adenoid cystic carcinoma: Incidence, variability, and clinicopathologic significance. Clinical Cancer Research, 16, 4722–4731. https://doi.org/10.1158/1078-0432.CCR-10-0463CrossRefPubMedPubMedCentral

44.

Bandopadhayay, P., Ramkissoon, L. A., Jain, P., Bergthold, G., Wala, J., Zeid, R., et al. (2016). MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nature Genetics, 48, 273–282. https://doi.org/10.1038/ng.3500CrossRefPubMedPubMedCentral

45.

Suh, Y. Y., Lee, K., Shim, Y. M., Phi, J. H., Park, C. K., Kim, S. K., et al. (2023). MYB/MYBL1::QKI fusion-positive diffuse glioma. Journal of Neuropathology and Experimental Neurology, 82, 250–260. https://doi.org/10.1093/jnen/nlac123CrossRefPubMedPubMedCentral

46.

Kim, J., Geyer, F. C., Martelotto, L. G., Ng, C. K., Lim, R. S., Selenica, P., et al. (2018). MYBL1 rearrangements and MYB amplification in breast adenoid cystic carcinomas lacking the MYB-NFIB fusion gene. The Journal of Pathology, 244, 143–150. https://doi.org/10.1002/path.5006CrossRefPubMed

47.

Mitani, Y., Liu, B., Rao, P. H., Borra, V. J., Zafereo, M., Weber, R. S., et al. (2016). Novel MYBL1 gene rearrangements with recurrent MYBL1-NFIB Fusions in salivary adenoid cystic carcinomas lacking t(6;9) translocations. Clinical Cancer Research, 22, 725–733. https://doi.org/10.1158/1078-0432.CCR-15-2867-TCrossRefPubMed

48.

Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. Cell, 144, 646–674. https://doi.org/10.1016/j.cell.2011.02.013CrossRefPubMed

49.

Kuehl, W. M., Bender, T. P., Stafford, J., McClinton, D., Segal, S., & Dmitrovsky, E. (1988). Expression and function of the c-myb oncogene during hematopoietic differentiation. Current Topics in Microbiology and Immunology, 141, 318–323. https://doi.org/10.1007/978-3-642-74006-0_42CrossRefPubMed

50.

Dyson, P. J., Poirier, F., & Watson, R. J. (1989). Expression of c-myb in embryonal carcinoma cells and embryonal stem cells. Differentiation, 42, 24–27. https://doi.org/10.1111/j.1432-0436.1989.tb00603.xCrossRefPubMed

51.

Introna, M., Luchetti, M., Castellano, M., Arsura, M., & Golay, J. (1994). The myb oncogene family of transcription factors: Potent regulators of hematopoietic cell proliferation and differentiation. Seminars in Cancer Biology, 5, 113–124.PubMed

52.

Huang, Y., Hong, W., & Wei, X. (2022). The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. Journal of Hematology & Oncology, 15, 129. https://doi.org/10.1186/s13045-022-01347-8CrossRef

53.

Karafiat, V., Dvorakova, M., Krejci, E., Kralova, J., Pajer, P., Snajdr, P., et al. (2005). Transcription factor c-Myb is involved in the regulation of the epithelial-mesenchymal transition in the avian neural crest. Cellular and Molecular Life Sciences, 62, 2516–2525. https://doi.org/10.1007/s00018-005-5297-7CrossRefPubMed

54.

Tanno, B., Sesti, F., Cesi, V., Bossi, G., Ferrari-Amorotti, G., Bussolari, R., et al. (2010). Expression of Slug is regulated by c-Myb and is required for invasion and bone marrow homing of cancer cells of different origin. Journal of Biological Chemistry, 285, 29434–29445. https://doi.org/10.1074/jbc.M109.089045CrossRefPubMedPubMedCentral

55.

Cesi, V., Casciati, A., Sesti, F., Tanno, B., Calabretta, B., & Raschella, G. (2011). TGFbeta-induced c-Myb affects the expression of EMT-associated genes and promotes invasion of ER+ breast cancer cells. Cell Cycle, 10, 4149–4161. https://doi.org/10.4161/cc.10.23.18346CrossRefPubMed

56.

Cheng, J., Wu, K., Yang, Q., Zhu, Z., & Zhao, H. (2023). RNF6 activates TGF-beta1/c-Myb pathway to promote EMT in esophageal squamous cell carcinoma. Frontiers in Oncology, 13, 1081333. https://doi.org/10.3389/fonc.2023.1081333CrossRefPubMedPubMedCentral

57.

Srivastava, S. K., Bhardwaj, A., Singh, S., Arora, S., McClellan, S., Grizzle, W. E., et al. (2012). Myb overexpression overrides androgen depletion-induced cell cycle arrest and apoptosis in prostate cancer cells, and confers aggressive malignant traits: Potential role in castration resistance. Carcinogenesis, 33, 1149–1157. https://doi.org/10.1093/carcin/bgs134CrossRefPubMedPubMedCentral

58.

Anand, S., Khan, M. A., Zubair, H., Sudan, S. K., Vikramdeo, K. S., Deshmukh, S. K., et al. (2023). MYB sustains hypoxic survival of pancreatic cancer cells by facilitating metabolic reprogramming. EMBO Reports, 24, e55643. https://doi.org/10.15252/embr.202255643CrossRefPubMedPubMedCentral

59.

Kim, D., You, E., Jeong, J., Ko, P., Kim, J. W., & Rhee, S. (2017). DDR2 controls the epithelial-mesenchymal-transition-related gene expression via c-Myb acetylation upon matrix stiffening. Scientific Reports, 7, 6847. https://doi.org/10.1038/s41598-017-07126-7CrossRefPubMedPubMedCentral

60.

Qu, X., Yan, X., Kong, C., Zhu, Y., Li, H., Pan, D., et al. (2019). c-Myb promotes growth and metastasis of colorectal cancer through c-fos-induced epithelial-mesenchymal transition. Cancer Science, 110, 3183–3196. https://doi.org/10.1111/cas.14141CrossRefPubMedPubMedCentral

61.

Xu, L. H., Zhao, F., Yang, W. W., Chen, C. W., Du, Z. H., Fu, M., et al. (2019). MYB promotes the growth and metastasis of salivary adenoid cystic carcinoma. International Journal of Oncology, 54, 1579–1590. https://doi.org/10.3892/ijo.2019.4754CrossRefPubMedPubMedCentral

62.

Wei, M., Yang, R., Ye, M., Zhan, Y., Liu, B., Meng, L., et al. (2022). MYBL2 accelerates epithelial-mesenchymal transition and hepatoblastoma metastasis via the Smad/SNAI1 pathway. American Journal of Cancer Research, 12, 1960–1981.PubMedPubMedCentral

63.

Tao, D., Pan, Y., Jiang, G., Lu, H., Zheng, S., Lin, H., et al. (2015). B-Myb regulates snail expression to promote epithelial-to-mesenchymal transition and invasion of breast cancer cell. Medical Oncology, 32, 412. https://doi.org/10.1007/s12032-014-0412-yCrossRefPubMed

64.

Fiscon, G., Pegoraro, S., Conte, F., Manfioletti, G., & Paci, P. (2021). Gene network analysis using SWIM reveals interplay between the transcription factor-encoding genes HMGA1, FOXM1, and MYBL2 in triple-negative breast cancer. FEBS Letters, 595, 1569–1586. https://doi.org/10.1002/1873-3468.14085CrossRefPubMed

65.

Xie, B., Liu, Y., Zhao, Z., Liu, Q., Wang, X., Xie, Y., et al. (2020). MYB proto-oncogene-like 1-TWIST1 axis promotes growth and metastasis of hepatocellular carcinoma cells. Molecular Therapy Oncolytics, 18, 58–69. https://doi.org/10.1016/j.omto.2020.05.016CrossRefPubMedPubMedCentral

66.

Thompson, C. B., Challoner, P. B., Neiman, P. E., & Groudine, M. (1986). Expression of the c-myb proto-oncogene during cellular proliferation. Nature, 319, 374–80. https://doi.org/10.1038/319374a0CrossRefPubMed

67.

Anfossi, G., Gewirtz, A. M., & Calabretta, B. (1989). An oligomer complementary to c-myb-encoded mRNA inhibits proliferation of human myeloid leukemia cell lines. Proceedings of the Nationsl Academy of Sciences U S A, 86, 3379–3383. https://doi.org/10.1073/pnas.86.9.3379CrossRef

68.

Drabsch, Y., Hugo, H., Zhang, R., Dowhan, D. H., Miao, Y. R., Gewirtz, A. M., et al. (2007). Mechanism of and requirement for estrogen-regulated MYB expression in estrogen-receptor-positive breast cancer cells. Proceedings of the National Academy Sciences U S A, 104, 13762–13767. https://doi.org/10.1073/pnas.0700104104CrossRef

69.

Miao, R. Y., Drabsch, Y., Cross, R. S., Cheasley, D., Carpinteri, S., Pereira, L., et al. (2011). MYB is essential for mammary tumorigenesis. Cancer Research, 71, 7029–7037. https://doi.org/10.1158/0008-5472.CAN-11-1015CrossRefPubMed

70.

Ye, P., Zhao, L., & Gonda, T. J. (2013). The MYB oncogene can suppress apoptosis in acute myeloid leukemia cells by transcriptional repression of DRAK2 expression. Leukemia Research, 37, 595–601. https://doi.org/10.1016/j.leukres.2013.01.012CrossRefPubMed

71.

Quintana, A. M., Liu, F., O’Rourke, J. P., & Ness, S. A. (2011). Identification and regulation of c-Myb target genes in MCF-7 cells. BMC Cancer, 11, 30. https://doi.org/10.1186/1471-2407-11-30CrossRefPubMedPubMedCentral

72.

Srivastava, S. K., Bhardwaj, A., Arora, S., Singh, S., Azim, S., Tyagi, N., et al. (2015). MYB is a novel regulator of pancreatic tumour growth and metastasis. British Journal of Cancer, 113, 1694–1703. https://doi.org/10.1038/bjc.2015.400CrossRefPubMedPubMedCentral

73.

Azim, S., Zubair, H., Srivastava, S. K., Bhardwaj, A., Zubair, A., Ahmad, A., et al. (2016). Deep sequencing and in silico analyses identify MYB-regulated gene networks and signaling pathways in pancreatic cancer. Scientific Reports, 6, 28446. https://doi.org/10.1038/srep28446CrossRefPubMedPubMedCentral

74.

Acharya, S., Anand, S., Khan, M. A., Zubair, H., Srivastava, S. K., Singh, S., et al. (2023). Biphasic transcriptional and posttranscriptional regulation of MYB by androgen signaling mediates its growth control in prostate cancer. Journal of Biological Chemistry, 299, 102725. https://doi.org/10.1016/j.jbc.2022.102725CrossRefPubMed

75.

Lyon, J., Robinson, C., & Watson, R. (1994). The role of Myb proteins in normal and neoplastic cell proliferation. Critical Reviews in Oncogenesis, 5, 373–388. https://doi.org/10.1615/critrevoncog.v5.i4.30CrossRefPubMed

76.

Liu, W., Shen, D., Ju, L., Zhang, R., Du, W., Jin, W., et al. (2022). MYBL2 promotes proliferation and metastasis of bladder cancer through transactivation of CDCA3. Oncogene, 41, 4606–4617. https://doi.org/10.1038/s41388-022-02456-xCrossRefPubMed

77.

Wei, T., Weiler, S. M. E., Toth, M., Sticht, C., Lutz, T., Thomann, S., et al. (2019). YAP-dependent induction of UHMK1 supports nuclear enrichment of the oncogene MYBL2 and proliferation in liver cancer cells. Oncogene, 38, 5541–5550. https://doi.org/10.1038/s41388-019-0801-yCrossRefPubMed

78.

Xiong, Y. C., Wang, J., Cheng, Y., Zhang, X. Y., & Ye, X. Q. (2020). Overexpression of MYBL2 promotes proliferation and migration of non-small-cell lung cancer via upregulating NCAPH. Molecular and Cellular Biochemistry, 468, 185–193. https://doi.org/10.1007/s11010-020-03721-xCrossRefPubMed

79.

Hanada, N., Lo, H. W., Day, C. P., Pan, Y., Nakajima, Y., & Hung, M. C. (2006). Co-regulation of B-Myb expression by E2F1 and EGF receptor. Molecular Carcinogenesis, 45, 10–17. https://doi.org/10.1002/mc.20147CrossRefPubMed

80.

Arsura, M., Introna, M., Passerini, F., Mantovani, A., & Golay, J. (1992). B-myb antisense oligonucleotides inhibit proliferation of human hematopoietic cell lines. Blood, 79, 2708–2716. https://doi.org/10.1182/blood.V79.10.2708.2708CrossRefPubMed

81.

Golay, J., Broccoli, V., Lamorte, G., Bifulco, C., Parravicini, C., Pizzey, A., et al. (1998). The A-Myb transcription factor is a marker of centroblasts in vivo. The Journal of Immunology, 160, 2786–2793. https://doi.org/10.4049/jimmunol.160.6.2786CrossRefPubMed

82.

Li, Y., Jin, K., van Pelt, G. W., van Dam, H., Yu, X., Mesker, W. E., et al. (2016). c-Myb enhances breast cancer invasion and metastasis through the Wnt/beta-catenin/axin2 pathway. Cancer Research, 76, 3364–3375. https://doi.org/10.1158/0008-5472.CAN-15-2302CrossRefPubMed

83.

Knopfova, L., Benes, P., Pekarcikova, L., Hermanova, M., Masarik, M., Pernicova, Z., et al. (2012). ”c-Myb regulates matrix metalloproteinases 1/9, and cathepsin D: implications for matrix-dependent breast cancer cell invasion and metastasis”. Molecular Cancer, 11, 15. https://doi.org/10.1186/1476-4598-11-15CrossRefPubMedPubMedCentral

84.

Tichy, M., Knopfova, L., Jarkovsky, J., Pekarcikova, L., Veverkova, L., Vlcek, P., et al. (2016). Overexpression of c-Myb is associated with suppression of distant metastases in colorectal carcinoma. Tumour Biology, 37, 10723–10729. https://doi.org/10.1007/s13277-016-4956-7CrossRefPubMed

85.

Y. Jin, H. Zhu, W. Cai, X. Fan, Y. Wang, Y. Niu, et al. (2017). "B-Myb is up-regulated and promotes cell growth and motility in non-small cell lung cancer," Int J Mol Sci, 18 https://doi.org/10.3390/ijms18060860

86.

Zhu, J., Wu, Y., Yu, Y., Li, Y., Shen, J., & Zhang, R. (2022). MYBL1 induces transcriptional activation of ANGPT2 to promote tumor angiogenesis and confer sorafenib resistance in human hepatocellular carcinoma. Cell Death Disease, 13, 727. https://doi.org/10.1038/s41419-022-05180-2CrossRefPubMedPubMedCentral

87.

Mansoori, B., Mohammadi, A., Davudian, S., Shirjang, S., & Baradaran, B. (2017). The different mechanisms of cancer drug resistance: a brief review. Advanced Pharmaceutical Bulletin, 7, 339–348. https://doi.org/10.15171/apb.2017.041CrossRefPubMedPubMedCentral

88.

Funato, T., Satou, J., Kozawa, K., Fujimaki, S., Miura, T., & Kaku, M. (2001). Use of c-myb antisense oligonucleotides to increase the sensitivity of human colon cancer cells to cisplatin. Oncology Reports, 8, 807–10. https://doi.org/10.3892/or.8.4.807CrossRefPubMed

89.

Tian, M., Tian, D., Qiao, X., Li, J., & Zhang, L. (2019). Modulation of Myb-induced NF-kB -STAT3 signaling and resulting cisplatin resistance in ovarian cancer by dietary factors. Journal of Cellular Physiology, 234, 21126–21134. https://doi.org/10.1002/jcp.28715CrossRefPubMed

90.

Gao, Y., Zhang, W., Liu, C., & Li, G. (2019). miR-200 affects tamoxifen resistance in breast cancer cells through regulation of MYB. Scientific Reports, 9, 18844. https://doi.org/10.1038/s41598-019-54289-6CrossRefPubMedPubMedCentral

91.

Yang, R. M., Nanayakkara, D., Kalimutho, M., Mitra, P., Khanna, K. K., Dray, E., et al. (2019). MYB regulates the DNA damage response and components of the homology-directed repair pathway in human estrogen receptor-positive breast cancer cells. Oncogene, 38, 5239–5249. https://doi.org/10.1038/s41388-019-0789-3CrossRefPubMed

92.

Wang, W., Wu, S., Shi, Y., Miao, Y., Luo, X., Ji, M., et al. (2015). c-MYB regulates cell growth and DNA damage repair through modulating MiR-143. FEBS Letters, 589, 555–564. https://doi.org/10.1016/j.febslet.2015.01.012CrossRefPubMed

93.

Pekarcikova, L., Knopfova, L., Benes, P., & Smarda, J. (2016). c-Myb regulates NOX1/p38 to control survival of colorectal carcinoma cells. Cellular Signalling, 28, 924–936. https://doi.org/10.1016/j.cellsig.2016.04.007CrossRefPubMed

94.

Siebzehnrubl, F. A., Silver, D. J., Tugertimur, B., Deleyrolle, L. P., Siebzehnrubl, D., Sarkisian, M. R., et al. (2013). The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance. EMBO Molecular Medicine, 5, 1196–1212. https://doi.org/10.1002/emmm.201302827CrossRefPubMedPubMedCentral

95.

P. Posdzich, C. Darr, T. Hilser, M. Wahl, K. Herrmann, B. Hadaschik, et al. (2023). "Metastatic Prostate cancer-a review of current treatment options and promising new approaches." Cancers (Basel), 15 https://doi.org/10.3390/cancers15020461.

96.

Chandrasekar, T., Yang, J. C., Gao, A. C., & Evans, C. P. (2015). Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Translational Andrology Urology, 4, 365–380. https://doi.org/10.3978/j.issn.2223-4683.2015.05.02CrossRefPubMedPubMedCentral

97.

Srivastava, S. K., Khan, M. A., Anand, S., Zubair, H., Deshmukh, S. K., Patel, G. K., et al. (2022). MYB interacts with androgen receptor, sustains its ligand-independent activation and promotes castration resistance in prostate cancer. British Journal of Cancer, 126, 1205–1214. https://doi.org/10.1038/s41416-021-01641-1CrossRefPubMed

98.

Miree, O., Srivastava, S. K., Khan, M. A., Sameeta, F., Acharya, S., Ndetan, H., et al. (2021). Clinicopathologic significance and race-specific prognostic association of MYB overexpression in ovarian cancer. Scientific Reports, 11, 12901. https://doi.org/10.1038/s41598-021-92352-3CrossRefPubMedPubMedCentral

99.

Yoshikawa, Y., Stopsack, K. H., Wang, X. V., Chen, Y. H., Mazzu, Y. Z., Burton, F., et al. (2022). Increased MYBL2 expression in aggressive hormone-sensitive prostate cancer. Molecular Oncology, 16, 3994–4010. https://doi.org/10.1002/1878-0261.13314CrossRefPubMedPubMedCentral

100.

Li, Q., Wang, M., Hu, Y., Zhao, E., Li, J., Ren, L., et al. (2021). MYBL2 disrupts the Hippo-YAP pathway and confers castration resistance and metastatic potential in prostate cancer. Theranostics, 11, 5794–5812. https://doi.org/10.7150/thno.56604CrossRefPubMedPubMedCentral

101.

Grassilli, E., Salomoni, P., Perrotti, D., Franceschi, C., & Calabretta, B. (1999). Resistance to apoptosis in CTLL-2 cells overexpressing B-Myb is associated with B-Myb-dependent bcl-2 induction. Cancer Research, 59, 2451–2456.PubMed

102.

Sala, A., Bettuzzi, S., Pucci, S., Chayka, O., Dews, M., & Thomas-Tikhonenko, A. (2009). Regulation of CLU gene expression by oncogenes and epigenetic factors implications for tumorigenesis. Advances in Cancer Research, 105, 115–132. https://doi.org/10.1016/S0065-230X(09)05007-6CrossRefPubMedPubMedCentral

103.

Li, X., Zhang, X., Wu, C. C., Li, P. P., Fu, Y. M., Xie, L. H., et al. (2021). The role of MYB proto-oncogene like 2 in tamoxifen resistance in breast cancer. Journal of Molecular Histology, 52, 21–30. https://doi.org/10.1007/s10735-020-09920-6CrossRefPubMed

104.

Chen, X., Lu, Y., Yu, H., Du, K., Zhang, Y., Nan, Y., et al. (2021). Pan-cancer analysis indicates that MYBL2 is associated with the prognosis and immunotherapy of multiple cancers as an oncogene. Cell Cycle, 20, 2291–2308. https://doi.org/10.1080/15384101.2021.1982494CrossRefPubMedPubMedCentral

105.

Morris, B. B., Wages, N. A., Grant, P. A., Stukenberg, P. T., Gentzler, R. D., Hall, R. D., et al. (2020). MYBL2-driven transcriptional programs link replication stress and error-prone DNA repair with genomic instability in lung adenocarcinoma. Frontiers in Oncology, 10, 585551. https://doi.org/10.3389/fonc.2020.585551CrossRefPubMed

106.

Qi, G., Zhang, C., Ma, H., Li, Y., Peng, J., Chen, J., et al. (2021). CDCA8, targeted by MYBL2, promotes malignant progression and olaparib insensitivity in ovarian cancer. American Journal of Cancer Research, 11, 389–415.PubMedPubMedCentral

107.

Bussard, K. M., Mutkus, L., Stumpf, K., Gomez-Manzano, C., & Marini, F. C. (2016). Tumor-associated stromal cells as key contributors to the tumor microenvironment. Breast Cancer Research, 18, 84. https://doi.org/10.1186/s13058-016-0740-2CrossRefPubMedPubMedCentral

108.

Sund, M., & Kalluri, R. (2009). Tumor stroma derived biomarkers in cancer. Cancer and Metastasis Reviews, 28, 177–183. https://doi.org/10.1007/s10555-008-9175-2CrossRefPubMed

109.

Bhardwaj, A., Srivastava, S. K., Singh, S., Tyagi, N., Arora, S., Carter, J. E., et al. (2016). MYB promotes desmoplasia in pancreatic cancer through direct transcriptional up-regulation and cooperative action of sonic hedgehog and adrenomedullin. Journal of Biological Chemistry, 291, 16263–16270. https://doi.org/10.1074/jbc.M116.732651CrossRefPubMedPubMedCentral

110.

Olive, K. P., Jacobetz, M. A., Davidson, C. J., Gopinathan, A., McIntyre, D., Honess, D., et al. (2009). Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science, 324, 1457–1461. https://doi.org/10.1126/science.1171362CrossRefPubMedPubMedCentral

111.

Shah, V. M., Sheppard, B. C., Sears, R. C., & Alani, A. W. (2020). Hypoxia: Friend or foe for drug delivery in pancreatic cancer. Cancer Letters, 492, 63–70. https://doi.org/10.1016/j.canlet.2020.07.041CrossRefPubMedPubMedCentral

112.

Yuen, A., & Diaz, B. (2014). The impact of hypoxia in pancreatic cancer invasion and metastasis. Hypoxia (Auckl), 2, 91–106. https://doi.org/10.2147/HP.S52636CrossRefPubMed

113.

Millen, R., Malaterre, J., Cross, R. S., Carpinteri, S., Desai, J., Tran, B., et al. (2016). Immunomodulation by MYB is associated with tumor relapse in patients with early stage colorectal cancer. Oncoimmunology, 5, e1149667. https://doi.org/10.1080/2162402X.2016.1149667CrossRefPubMedPubMedCentral

114.

Watt, J., & Kocher, H. M. (2013). The desmoplastic stroma of pancreatic cancer is a barrier to immune cell infiltration. Oncoimmunology, 2, e26788. https://doi.org/10.4161/onci.26788CrossRefPubMedPubMedCentral

115.

Xiao, Z., Todd, L., Huang, L., Noguera-Ortega, E., Lu, Z., Huang, L., et al. (2023). Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors. Nature Communications, 14, 5110. https://doi.org/10.1038/s41467-023-40850-5CrossRefPubMedPubMedCentral

116.

Chen, I. X., Chauhan, V. P., Posada, J., Ng, M. R., Wu, M. W., Adstamongkonkul, P., et al. (2019). Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer. Proceeding of the National Academy Sciences U S A, 116, 4558–4566. https://doi.org/10.1073/pnas.1815515116CrossRef

117.

Biasci, D., Smoragiewicz, M., Connell, C. M., Wang, Z., Gao, Y., Thaventhiran, J. E. D., et al. (2020). CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response. Proceedings of the National Academy Sciences U S A, 117, 28960–28970. https://doi.org/10.1073/pnas.2013644117CrossRef

118.

Coppe, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: The dark side of tumor suppression. Annual Review of Pathology: Mechanisms of Disease, 5, 99–118. https://doi.org/10.1146/annurev-pathol-121808-102144CrossRef

119.

Flanagan, K. C., Alspach, E., Pazolli, E., Parajuli, S., Ren, Q., Arthur, L. L., et al. (2018). c-Myb and C/EBPbeta regulate OPN and other senescence-associated secretory phenotype factors. Oncotarget, 9, 21–36. https://doi.org/10.18632/oncotarget.22940CrossRefPubMed

120.

Wu, X., Tao, P., Zhou, Q., Li, J., Yu, Z., Wang, X., et al. (2017). IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway. Oncotarget, 8, 20741–20750. https://doi.org/10.18632/oncotarget.15119CrossRefPubMedPubMedCentral

121.

K. Jin, N. B. Pandey, and A. S. Popel 2017 "Crosstalk between stromal components and tumor cells of TNBC via secreted factors enhances tumor growth and metastasis." Oncotarget 8, 60210–60222 https://doi.org/10.18632/oncotarget.19417

122.

Ringleb, J., Strack, E., Angioni, C., Geisslinger, G., Steinhilber, D., Weigert, A., et al. (2018). Apoptotic cancer cells suppress 5-lipoxygenase in tumor-associated macrophages. The Journal of Immunology, 200, 857–868. https://doi.org/10.4049/jimmunol.1700609CrossRefPubMed

Title: From modulation of cellular plasticity to potentiation of therapeutic resistance: new and emerging roles of MYB transcription factors in human malignancies
Authors: Shashi Anand
Kunwar Somesh Vikramdeo
Sarabjeet Kour Sudan
Amod Sharma
Srijan Acharya
Mohammad Aslam Khan
Seema Singh
Ajay Pratap Singh
Publication date: 10-11-2023
Publisher: Springer US
Published in: Cancer and Metastasis Reviews / Issue 1/2024
Print ISSN: 0167-7659
Electronic ISSN: 1573-7233
DOI: https://doi.org/10.1007/s10555-023-10153-8

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2024

Harnessing function of EMT in cancer drug resistance: a metastasis regulator determines chemotherapy response

Sam68 is a druggable vulnerability point in cancer stem cells

Clusterin: a marker and mediator of chemoresistance in colorectal cancer

Cell plasticity modulation by flavonoids in resistant breast carcinoma targeting the nuclear factor kappa B signaling

Cancer cell plasticity, stem cell factors, and therapy resistance: how are they linked?

Modulation of hypoxia-inducible factor-1 signaling pathways in cancer angiogenesis, invasion, and metastasis by natural compounds: a comprehensive and critical review

Keynote webinar | Spotlight on antibody–drug conjugates in cancer