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The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the NCOA3 gene.[5][6] NCOA3 is also frequently called ‘amplified in breast 1’ (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone receptor activator molecule 1 (TRAM-1).

Function

NCOA3 is a transcriptional coactivator protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA3 is recruited to DNA promotion sites by ligand-activated nuclear receptors. NCOA3, in turn, acylates histones, which makes downstream DNA more accessible to transcription. Hence, NCOA3 assists nuclear receptors in the upregulation of gene expression.[7][8]

Clinical significance

The ratio of PAX2 to AIB-1 protein expression may be predictive of the effectiveness of tamoxifen in breast cancer treatment.[9][10]

Several molecular mechanisms implicate NCOA3 (AIB1) in the endocrine therapy resistance (depicted in the figure). Signaling pathways or mutations (i.e. HER2/neu overexpression, activating mutations in PIK3CA (PI3K), activating mutations in the proto-oncogene tyrosine-protein kinase Src, etc.) that lead to persistent activation of ERK and/or PIK3CA/AKT kinase pathways result, in one hand in an enhanced AIB1 transcriptional coactivation capacity,[11] and in the other hand in the inhibition of the proteasome-dependent AIB1 turn-over and therefore, in AIB1 overexpression.[12] In both conditions, the equilibrium of estrogen receptor (ER) complex formation is displaced towards a transcriptionally active complex and thus, counteracting the inhibition caused by anti-estrogenic drugs such as tamoxifen or fulvestrant (selective estrogen receptor modulators). The result is the restoration of estrogen-sensitive gene transcription and the promotion of cancer progression and/or relapse.

Notably, tumors diagnosed with concomitant overexpression of AIB1 and HER2/neu have worse outcome with tamoxifen therapy than all other patients combined.[13] In addition, dormant tumor cells of luminal breast cancers treated with endocrine therapy may acquire with time, mutations that alter kinase signalling pathways and ultimately enhance AIB1 oncogenic functions. Also, estrogen receptor-PAX2 complexes repress HER2/neu expression, but loss of PAX2 expression may result in de novo HER2/neu expression and initiate endocrine therapy resistance and relapse.[14]

Mechanisms for AIB1-dependent anti-estrogen therapy resistance

Interactions

Nuclear receptor coactivator 3 has been shown to interact with:

Nuclear Factor Kappa B, [27]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000124151 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027678 – Ensembl, May 2017
  3. ^ “Human PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ “Mouse PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, et al. (August 1997). “AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer”. Science. 277 (5328): 965–968. doi:10.1126/science.277.5328.965. PMID 9252329.
  6. ^ Takeshita A, Cardona GR, Koibuchi N, Suen CS, Chin WW (October 1997). “TRAM-1, A novel 160-kDa thyroid hormone receptor activator molecule, exhibits distinct properties from steroid receptor coactivator-1”. The Journal of Biological Chemistry. 272 (44): 27629–27634. doi:10.1074/jbc.272.44.27629. PMID 9346901.
  7. ^ Anzick SL, Kononen J, Walker RL, Azorsa DO, Tanner MM, Guan XY, et al. (1997). “AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer”. Science. 277 (5328): 965–968. doi:10.1126/science.277.5328.965. PMID 9252329.
  8. ^ Takeshita A, Cardona GR, Koibuchi N, Suen CS, Chin WW (1997). “TRAM-1, A novel 160-kDa thyroid hormone receptor activator molecule, exhibits distinct properties from steroid receptor coactivator-1”. The Journal of Biological Chemistry. 272 (44): 27629–27634. doi:10.1074/jbc.272.44.27629. PMID 9346901.
  9. ^ “Study sheds new light on tamoxifen resistance”. Cordis News. Cordis. 2008-11-13. Archived from the original on 2009-02-20. Retrieved 2008-11-14.
  10. ^ Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, et al. (December 2008). “Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen”. Nature. 456 (7222): 663–666. Bibcode:2008Natur.456..663H. doi:10.1038/nature07483. PMC 2920208. PMID 19005469.
  11. ^ Font de Mora J, Brown M (July 2000). “AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor”. Molecular and Cellular Biology. 20 (14): 5041–5047. doi:10.1128/MCB.20.14.5041-5047.2000. PMC 85954. PMID 10866661.
  12. ^ Ferrero M, Avivar A, García-Macías MC, Font de Mora J (July 2008). “Phosphoinositide 3-kinase/AKT signaling can promote AIB1 stability independently of GSK3 phosphorylation”. Cancer Research. 68 (13): 5450–5459. doi:10.1158/0008-5472.CAN-07-6433. PMID 18593948.
  13. ^ Osborne CK, Bardou V, Hopp TA, Chamness GC, Hilsenbeck SG, Fuqua SA, et al. (March 2003). “Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer”. Journal of the National Cancer Institute. 95 (5): 353–361. doi:10.1093/jnci/95.5.353. PMID 12618500.
  14. ^ Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, et al. (December 2008). “Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen”. Nature. 456 (7222): 663–666. Bibcode:2008Natur.456..663H. doi:10.1038/nature07483. PMC 2920208. PMID 19005469.
  15. ^ Tan JA, Hall SH, Petrusz P, French FS (September 2000). “Thyroid receptor activator molecule, TRAM-1, is an androgen receptor coactivator”. Endocrinology. 141 (9): 3440–3450. doi:10.1210/endo.141.9.7680. PMID 10965917.
  16. ^ Gnanapragasam VJ, Leung HY, Pulimood AS, Neal DE, Robson CN (December 2001). “Expression of RAC 3, a steroid hormone receptor co-activator in prostate cancer”. British Journal of Cancer. 85 (12): 1928–1936. doi:10.1054/bjoc.2001.2179. PMC 2364015. PMID 11747336.
  17. ^ Wang Q, Udayakumar TS, Vasaitis TS, Brodie AM, Fondell JD (April 2004). “Mechanistic relationship between androgen receptor polyglutamine tract truncation and androgen-dependent transcriptional hyperactivity in prostate cancer cells”. The Journal of Biological Chemistry. 279 (17): 17319–17328. doi:10.1074/jbc.M400970200. PMID 14966121.
  18. ^ a b c d Wu RC, Qin J, Hashimoto Y, Wong J, Xu J, Tsai SY, et al. (May 2002). “Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) Coactivator activity by I kappa B kinase”. Molecular and Cellular Biology. 22 (10): 3549–3561. doi:10.1128/MCB.22.10.3549-3561.2002. PMC 133790. PMID 11971985.
  19. ^ Naltner A, Wert S, Whitsett JA, Yan C (December 2000). “Temporal/spatial expression of nuclear receptor coactivators in the mouse lung”. American Journal of Physiology. Lung Cellular and Molecular Physiology. 279 (6) L1066-74. doi:10.1152/ajplung.2000.279.6.l1066. PMID 11076796. S2CID 27872061.
  20. ^ a b Wong CW, Komm B, Cheskis BJ (June 2001). “Structure-function evaluation of ER alpha and beta interplay with SRC family coactivators. ER selective ligands”. Biochemistry. 40 (23): 6756–6765. doi:10.1021/bi010379h. PMID 11389589.
  21. ^ Tikkanen MK, Carter DJ, Harris AM, Le HM, Azorsa DO, Meltzer PS, et al. (November 2000). “Endogenously expressed estrogen receptor and coactivator AIB1 interact in MCF-7 human breast cancer cells”. Proceedings of the National Academy of Sciences of the United States of America. 97 (23): 12536–12540. Bibcode:2000PNAS…9712536T. doi:10.1073/pnas.220427297. PMC 18799. PMID 11050174.
  22. ^ Leo C, Li H, Chen JD (February 2000). “Differential mechanisms of nuclear receptor regulation by receptor-associated coactivator 3”. The Journal of Biological Chemistry. 275 (8): 5976–5982. doi:10.1074/jbc.275.8.5976. PMID 10681591.
  23. ^ Hsiao PW, Fryer CJ, Trotter KW, Wang W, Archer TK (September 2003). “BAF60a mediates critical interactions between nuclear receptors and the BRG1 chromatin-remodeling complex for transactivation”. Molecular and Cellular Biology. 23 (17): 6210–6220. doi:10.1128/MCB.23.17.6210-6220.2003. PMC 180928. PMID 12917342.
  24. ^ Zilliacus J, Holter E, Wakui H, Tazawa H, Treuter E, Gustafsson JA (April 2001). “Regulation of glucocorticoid receptor activity by 14–3-3-dependent intracellular relocalization of the corepressor RIP140”. Molecular Endocrinology. 15 (4): 501–511. doi:10.1210/mend.15.4.0624. PMID 11266503.
  25. ^ Chen H, Lin RJ, Schiltz RL, Chakravarti D, Nash A, Nagy L, et al. (August 1997). “Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300”. Cell. 90 (3): 569–580. doi:10.1016/S0092-8674(00)80516-4. PMID 9267036. S2CID 15284825.
  26. ^ Lee WY, Noy N (February 2002). “Interactions of RXR with coactivators are differentially mediated by helix 11 of the receptor’s ligand binding domain”. Biochemistry. 41 (8): 2500–2508. doi:10.1021/bi011764+. PMID 11851396.
  27. ^ Werbajh S, Nojek I, Lanz R, Costas MA (November 2000). “RAC-3 is a NF-kappa B coactivator”. FEBS Letters. 485 (2–3): 195–199. doi:10.1016/S0014-5793(00)02223-7. PMID 11094166.

Further reading