Volume 10 Issue 3
Mar.  2019
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Wei Shao, Shasha Li, Lu Li, Kequan Lin, Xinhong Liu, Haiyan Wang, Huili Wang, Dong Wang. Chemical genomics reveals inhibition of breast cancer lung metastasis by Ponatinib via c-Jun[J]. Protein&Cell, 2019, 10(3): 161-177. doi: 10.1007/s13238-018-0533-8
Citation: Wei Shao, Shasha Li, Lu Li, Kequan Lin, Xinhong Liu, Haiyan Wang, Huili Wang, Dong Wang. Chemical genomics reveals inhibition of breast cancer lung metastasis by Ponatinib via c-Jun[J]. Protein&Cell, 2019, 10(3): 161-177. doi: 10.1007/s13238-018-0533-8

Chemical genomics reveals inhibition of breast cancer lung metastasis by Ponatinib via c-Jun

doi: 10.1007/s13238-018-0533-8
  • Received Date: 2018-02-06
  • Metastasis is the leading cause of human cancer deaths. Unfortunately, no approved drugs are available for antimetastatic treatment. In our study, high-throughput sequencing-based high-throughput screening (HTS2) and a breast cancer lung metastasis (BCLM)-associated gene signature were combined to discover anti-metastatic drugs. After screening of thousands of compounds, we identified Ponatinib as a BCLM inhibitor. Ponatinib significantly inhibited the migration and mammosphere formation of breast cancer cells in vitro and blocked BCLM in multiple mouse models. Mechanistically, Ponatinib represses the expression of BCLM-associated genes mainly through the ERK/c-Jun signaling pathway by inhibiting the transcription of JUN and accelerating the degradation of c-Jun protein. Notably, JUN expression levels were positively correlated with BCLM-associated gene expression and lung metastases in breast cancer patients. Collectively, we established a novel approach for the discovery of anti-metastatic drugs, identified Ponatinib as a new drug to inhibit BCLM and revealed c-Jun as a crucial factor and potential drug target for BCLM. Our study may facilitate the therapeutic treatment of BCLM as well as other metastases.
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  • [1]
    Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ, Jonat C, Herrlich P, Karin M (1987) Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell 49:729–739
    [2]
    Ayers M, Symmans WF, Stec J, Damokosh AI, Clark E, Hess K, Lecocke M, Metivier J, Booser D, Ibrahim N et al (2004) Gene expression profiles predict complete pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer. J Clin Oncol 22:2284–2293
    [3]
    Birkedal-Hansen H, Moore WG, Bodden MK, Windsor LJ, BirkedalHansen B, DeCarlo A, Engler JA (1993) Matrix metalloproteinases: a review. Crit Rev Oral Biol Med 4:197–250
    [4]
    Bos PD, Zhang XH, Nadal C, Shu W, Gomis RR, Nguyen DX, Minn AJ, van de Vijver MJ, Gerald WL, Foekens JA et al (2009) Genes that mediate breast cancer metastasis to the brain. Nature 459:1005–1009
    [5]
    Casey T, Bond J, Tighe S, Hunter T, Lintault L, Patel O, Eneman J, Crocker A, White J, Tessitore J et al (2009) Molecular signatures suggest a major role for stromal cells in development of invasive breast cancer. Breast Cancer Res Treat 114:47–62
    [6]
    Chambers J, Angulo A, Amaratunga D, Guo H, Jiang Y, Wan JS, Bittner A, Frueh K, Jackson MR, Peterson PA et al (1999) DNA microarrays of the complex human cytomegalovirus genome:profiling kinetic class with drug sensitivity of viral gene expression. J Virol 73:5757–5766
    [7]
    Chen H, Zhu G, Li Y, Padia RN, Dong Z, Pan ZK, Liu K, Huang S (2009) Extracellular signal-regulated kinase signaling pathway regulates breast cancer cell migration by maintaining slug expression. Cancer Res 69:9228–9235
    [8]
    Clarke C, Madden SF, Doolan P, Aherne ST, Joyce H, O’Driscoll L, Gallagher WM, Hennessy BT, Moriarty M, Crown J et al (2013)
    [9]
    Correlating transcriptional networks to breast cancer survival: a large-scale coexpression analysis. Carcinogenesis 34:2300– 2308
    [10]
    Gupta GP, Nguyen DX, Chiang AC, Bos PD, Kim JY, Nadal C, Gomis RR, Manova-Todorova K, Massague J (2007) Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature 446:765–770
    [11]
    Harrell JC, Prat A, Parker JS, Fan C, He X, Carey L, Anders C, Ewend M, Perou CM (2012) Genomic analysis identifies unique signatures predictive of brain, lung, and liver relapse. Breast Cancer Res Treat 132:523–535
    [12]
    Horak CE, Pusztai L, Xing G, Trifan OC, Saura C, Tseng LM, Chan S, Welcher R, Liu D (2013) Biomarker analysis of neoadjuvant doxorubicin/cyclophosphamide followed by ixabepilone or Paclitaxel in early-stage breast cancer. Clin Cancer Res 19:1587– 1595
    [13]
    Howe LR, Chang SH, Tolle KC, Dillon R, Young LJ, Cardiff RD, Newman RA, Yang P, Thaler HT, Muller WJ et al (2005) HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-2 knockout mice. Cancer Res 65:10113–10119
    [14]
    Iorio F, Bosotti R, Scacheri E, Belcastro V, Mithbaokar P, Ferriero R, Murino L, Tagliaferri R, Brunetti-Pierri N, Isacchi A et al (2010) Discovery of drug mode of action and drug repositioning from transcriptional responses. Proc Natl Acad Sci USA 107:14621– 14626
    [15]
    Kang Y, Siegel PM, Shu W, Drobnjak M, Kakonen SM, CordonCardo C, Guise TA, Massague J (2003) A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 3:537– 549
    [16]
    Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, Lerner J, Brunet JP, Subramanian A, Ross KN et al (2006) The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313:1929–1935
    [17]
    Landemaine T, Jackson A, Bellahcene A, Rucci N, Sin S, Abad BM, Sierra A, Boudinet A, Guinebretiere JM, Ricevuto E et al (2008) A six-gene signature predicting breast cancer lung metastasis.Cancer Res 68:6092–6099
    [18]
    Le Jan S, Amy C, Cazes A, Monnot C, Lamande N, Favier J, Philippe J, Sibony M, Gasc JM, Corvol P et al (2003) Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma. Am J Pathol 162:1521– 1528
    [19]
    Lee YT (1983) Breast carcinoma: pattern of metastasis at autopsy. J Surg Oncol 23:175–180
    [20]
    Lee J, Liu J, Feng X, Salazar Hernandez MA, Mucka P, Ibi D, Choi JW, Ozcan U (2016) Withaferin A is a leptin sensitizer with strong antidiabetic properties in mice. Nat Med 22:1023–1032
    [21]
    Li H, Qiu J, Fu XD (2012a) RASL-seq for massively parallel and quantitative analysis of gene expression. Curr Protoc Mol Biol.https://doi.org/10.1002/0471142727.mb0413s98
    [22]
    Li H, Zhou H, Wang D, Qiu J, Zhou Y, Li X, Rosenfeld MG, Ding S, Fu XD (2012b) Versatile pathway-centric approach based on high-throughput sequencing to anticancer drug discovery. Proc Natl Acad Sci USA 109:4609–4614
    [23]
    Li Q, Wang Y, Xiao H, Li Y, Kan X, Wang X, Zhang G, Wang Z, Yang Q, Chen X et al (2016) Chamaejasmenin B, a novel candidate, inhibits breast tumor metastasis by rebalancing TGF-beta paradox. Oncotarget 7:48180–48192
    [24]
    Lopez-Bergami P, Lau E, Ronai Z (2010) Emerging roles of ATF2 and the dynamic AP1 network in cancer. Nat Rev Cancer 10:65– 76
    [25]
    Lu X, Lu X, Kang Y (2010) Organ-specific enhancement of metastasis by spontaneous ploidy duplication and cell size enlargement. Cell Res 20:1012–1022
    [26]
    Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, Viale A, Olshen AB, Gerald WL, Massague J (2005) Genes that mediate breast cancer metastasis to lung. Nature 436:518–524
    [27]
    Morrison DK (2012) MAP kinase pathways. Cold Spring Harb Perspect Biol 4:a011254
    [28]
    Nguyen DX, Bos PD, Massague J (2009) Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 9:274–284
    [29]
    O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q et al (2009) AP24534, a panBCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.Cancer Cell 16:401–412
    [30]
    Oskarsson T, Acharyya S, Zhang XH, Vanharanta S, Tavazoie SF, Morris PG, Downey RJ, Manova-Todorova K, Brogi E, Massague J (2011) Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med 17:867–874
    [31]
    Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR, Massague J (2008) TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133:66–77
    [32]
    Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA et al (2000) Molecular portraits of human breast tumours. Nature 406:747– 752
    [33]
    Quiet CA, Ferguson DJ, Weichselbaum RR, Hellman S (1995) Natural history of node-negative breast cancer: a study of 826 patients with long-term follow-up. J Clin Oncol 13:1144–1151
    [34]
    Raney BJ, Cline MS, Rosenbloom KR, Dreszer TR, Learned K, Barber GP, Meyer LR, Sloan CA, Malladi VS, Roskin KM et al(2011) ENCODE whole-genome data in the UCSC genome browser (2011 update). Nucleic Acids Res 39:D871–875
    [35]
    Saito S, Furuno A, Sakurai J, Sakamoto A, Park HR, Shin-Ya K, Tsuruo T, Tomida A (2009) Chemical genomics identifies the unfolded protein response as a target for selective cancer cell killing during glucose deprivation. Cancer Res 69:4225–4234
    [36]
    Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67:7–30
    [37]
    Stegmaier K, Ross KN, Colavito SA, O’Malley S, Stockwell BR, Golub TR (2004) Gene expression-based high-throughput screening (GE-HTS) and application to leukemia differentiation.Nat Genet 36:257–263
    [38]
    Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES et al(2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102:15545–15550
    [39]
    Subramanian A, Narayan R, Corsello SM, Peck DD, Natoli TE, Lu X, Gould J, Davis JF, Tubelli AA, Asiedu JK et al (2017) A next generation connectivity map: L1000 platform and the first 1,000,000 profiles. Cell 171:1437–1452
    [40]
    Thakur R, Trivedi R, Rastogi N, Singh M, Mishra DP (2015) Inhibition of STAT3, FAK and Src mediated signaling reduces cancer stem cell load, tumorigenic potential and metastasis in breast cancer.Sci Rep 5:10194
    [41]
    van’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT et al(2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536
    [42]
    Wang LH, Xiang J, Yan M, Zhang Y, Zhao Y, Yue CF, Xu J, Zheng FM, Chen JN, Kang Z et al (2010) The mitotic kinase Aurora-A induces mammary cell migration and breast cancer metastasis by activating the Cofilin-F-actin pathway. Cancer Res 70:9118–9128
    [43]
    Wang J, Rouse C, Jasper JS, Pendergast AM (2016) ABL kinases promote breast cancer osteolytic metastasis by modulating tumor-bone interactions through TAZ and STAT5 signaling. Sci Signal 9:ra12
    [44]
    Weigelt B, Peterse JL, van’t Veer LJ (2005) Breast cancer metastasis: markers and models. Nat Rev Cancer 5:591–602
    [45]
    Wu Y, Zhang Y, Zhang H, Yang X, Wang Y, Ren F, Liu H, Zhai Y, Jia B, Yu J et al (2010) p15RS attenuates Wnt/β-catenin signaling by disrupting β-catenin-TCF4 interaction. J Biol Chem 285:34621– 34631
    [46]
    Xiu YL, Sun KX, Chen X, Chen S, Zhao Y, Guo QG, Zong ZH (2017)Upregulation of the lncRNA Meg3 induces autophagy to inhibit tumorigenesis and progression of epithelial ovarian carcinoma by regulating activity of ATG3. Oncotarget 8:31714–31725
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