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Guo S , Hakimi MA , Baillat D , Chen X , Farber MJ , Klein-Szanto AJP , Cooch NS , Godwin AK , Shiekhattar R
Linking transcriptional elongation and messenger RNA export to metastatic breast cancers
Cancer Research. 2005 ;65(8) :3011-3016
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Abstract
The biochemical pathways that are disrupted in the genesis of sporadic breast cancers remain unclear. Moreover, the present prognosticating markers used to determine the prognosis of node-negative patient leads to probabilistic results, and the eventual clinical course is far from certain. Here we identified the human TREX complex, a multiprotein complex that links transcription elongation to mRNA transport, as culprit of aggressive human breast cancers. We show that whereas p84N5 (called hTREX84) is expressed at very low levels in normal breast epithelial cells, it is highly expressed in breast tumors. Importantly, hTREX84 expression correlates with tumor size and the metastatic state of the tumor progression. Reduction of hTKEX84 levels in breast cancer cell lines by small interfering RNA result in inhibition of cellular proliferation and abrogation of mRNA export. These results not only identify hTREX84 as a prognosticator of breast cancer but also delineate human TREX complex as a target for therapeutic drugs against breast cancer. ©2005 American Association for Cancer Research.
Notes
00085472 (ISSN) Cited By: 1; Export Date: 25 May 2006; Source: Scopus CODEN: CNREA Language of Original Document: English Correspondence Address: Shiekhattar, R.; Wistar Institute; 3601 Spruce Street Philadelphia, PA 19104, United States; email: Shiekhattar@wistar.upenn.edu Chemicals/CAS: carrier protein, 80700-39-6, Cell Cycle Proteins; N5 protein, human; Nuclear Proteins; RNA, Messenger; RNA, Small Interfering; Transcriptional Elongation Factors References: Ramaswamy, S., Ross, K.N., Lander, E.S., Golub, T.R., A molecular signature of metastasis in primary solid tumors (2003) Nat Gene, 33, pp. 49-54; Van't Verr, L.J., Dai, H., Van De Vijver, M.J., Gene expression profiling predicts clinical outcome of breast cancer (2002) Nature, 415, pp. 530-536; Esteva, F.J., Hortobagyi, G.N., Prognostic molecular markers in early breast cancer (2004) Breast Cancer Res, 6, pp. 109-118; Bloom, H.J.G., Richardson, W.W., Histological grading and prognosis in cancer. A study of 1409 cases of which 359 have been followed for 15 years (1957) Br J Cancer, 11, pp. 359-377; Elston, C.W., Ellis, I.O., Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: Experience from a large study with long term follow-up (1991) Histopathology, 19, pp. 403-410; Bruening, W., Giasson, B.I., Klein-Szanto, A.J., Lee, V.M., Trojanowski, J.Q., Godwin, A.K., Synucleins are expressed in the majority of breast and ovarian carcinomas and in preneoplastic lesions of the ovary (2000) Cancer, 88, pp. 2154-2163; Dong, Y., Hakimi, M.A., Chen, X., Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair (2003) Mol Cell, 12, pp. 1087-1099; Russo, J., Calaf, G., Russo, I.H., A critical approach to the malignant transformation of human breast epithelial cells (1993) Crit Rev Oncog, 4, pp. 403-407; Russo, J., Russo, I.H., Development of the human breast (1998) Encyclopedia of Reproduction, 3, pp. 71-80, Knobil E and Neill JD, editors. New York: Academic Press; Frolov, A., Chahwan, S., Ochs, M., Response markers and the molecular mechanisms of action of Gleevec in gastrointestinal stromal tumors (2003) Mol Cancer Ther, 2, pp. 699-709; Durfee, T., Mancini, M.A., Jones, D., Elledge, S.J., Lee, W.H., The amino-terminal region of the retinoblastoma gene product binds a novel nuclear matrix protein that colocalizes to centers for RNA processing (1994) J Cell Biol, 127, pp. 609-622; Doostzadeh-Cizeron, J., Evans, R., Yin, S., Goodrich, D.W., Apoptosis induced by the nuclear death domain protein p84N5 is inhibited by association with Rb protein (1999) Mol Biol Cell, 10, pp. 3251-3261; Strasser, K., TREX is a conserved complex coupling transcription with messenger RNA export (2002) Nature, 417, pp. 304-308; Jimeno, S., Rondon, A.G., Luna, R., Aguilera, A., The yeast THO complex and mRNA export factors link RNA metabolism with transcription and genome instability (2002) EMBO J, 21, pp. 3526-3535.