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LIN9 confers paclitaxel resistance in triple negative breast cancer cells by upregulating CCSAP

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Abstract

LIN9 functions to regulate cell mitotic process. Dysregulation of LIN9 expression is associated with development of human cancers. In this study we assessed the association of LIN9 expression with paclitaxel resistance and clarified the underlying mechanisms for the first time. LIN9 expression in breast cancer tissues was retrieved from publicly available online databases and statistically analyzed. Human TNBC cell lines MDA-MB-231 and MDA-MB-468 and their corresponding paclitaxel-resistant sublines 231PTX and 468PTX were used to assess the expression of LIN9 by qRT-PCR and Western blot, cell growth by cell counting, cell viability by MTS assay, and cell apoptosis by flow cytometry. The data showed that high LIN9 expression in breast cancer patients receiving chemotherapy was related to poor overall survival (OS). LIN9 expression was upregulated in paclitaxel-resistant TNBC cells compared to their parental cells. Knockdown of LIN9 or treatment of paclitaxel-resistant TNBC cells with a bromo- and extra-terminal domain inhibitor (BETi) JQ1 which also decreased LIN9 expression enhanced the sensitivity of paclitaxel-resistant TNBC cells to paclitaxel. Mechanistically, decreased LIN9 in resistant cell lines reduced tumor cell viability, promoted multinucleated cells formation and induced tumor cell apoptosis, potentially by directly regulating microtubule-binding protein CCSAP. In conclusion, high LIN9 expression contributed to poor clinical outcomes and paclitaxel resistance in TNBC and BETi, targeting LIN9 expression, could be a reversible drug for PTX-resistant TNBC patients.

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References

  • Amorim, S., Stathis, A., Gleeson, M., Iyengar, S., Magarotto, V., Leleu, X., Morschhauser, F., Karlin, L., Broussais, F., Rezai, K., et al. (2016). Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study. Lancet Haematol 3, e196–e204.

    Article  Google Scholar 

  • Asangani, I.A., Dommeti, V.L., Wang, X., Malik, R., Cieslik, M., Yang, R., Escara-Wilke, J., Wilder-Romans, K., Dhanireddy, S., Engelke, C., et al. (2014). Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 510, 278–282.

    Article  CAS  Google Scholar 

  • Begley, U., Sosa, M.S., Avivar-Valderas, A., Patil, A., Endres, L., Estrada, Y., Chan, C.T.Y., Su, D., Dedon, P.C., Aguirre-Ghiso, J.A., et al. (2013). A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-α. EMBO Mol Med 5, 366–383.

    Article  CAS  Google Scholar 

  • Berthon, C., Raffoux, E., Thomas, X., Vey, N., Gomez-Roca, C., Yee, K., Taussig, D.C., Rezai, K., Roumier, C., Herait, P., et al. (2016). Bromodomain inhibitor OTX015 in patients with acute leukaemia: a dose-escalation, phase 1 study. Lancet Haematol 3, e186–e195.

    Article  Google Scholar 

  • Bian, M.L., Fu, J.Y., Yan, Y., Chen, Q., Yang, C., Shi, Q.H., Jiang, Q., and Zhang, C.M. (2010). Short exposure to paclitaxel induces multipolar spindle formation and aneuploidy through promotion of acentrosomal pole assembly. Sci China Life Sci 53, 1322–1329.

    Article  CAS  Google Scholar 

  • Calvisi, D.F., Simile, M.M., Ladu, S., Frau, M., Evert, M., Tomasi, M.L., Demartis, M.I., Daino, L., Seddaiu, M.A., Brozzetti, S., et al. (2011). Activation of v-Myb avian myeloblastosis viral oncogene homolog-like2 (MYBL2)-LIN9 complex contributes to human hepatocarcinogenesis and identifies a subset of hepatocellular carcinoma with mutant p53. Hepatology 53, 1226–1236.

    Article  CAS  Google Scholar 

  • Casazza, A.M., and Fairchild, C.R. (1996). Paclitaxel (Taxol): mechanisms of resistance. Cancer Treat Res 87, 149–171.

    Article  CAS  Google Scholar 

  • Cortes, J., O’Shaughnessy, J., Loesch, D., Blum, J.L., Vahdat, L.T., Petrakova, K., Chollet, P., Manikas, A., Diéras, V., Delozier, T., et al. (2011). Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 377, 914–923.

    Article  CAS  Google Scholar 

  • de Ruijter, T.C., Veeck, J., de Hoon, J.P.J., van Engeland, M., and Tjan-Heijnen, V.C. (2011). Characteristics of triple-negative breast cancer. J Cancer Res Clin Oncol 137, 183–192.

    Article  Google Scholar 

  • DeCaprio, J.A. (2014). Human papillomavirus type 16 E7 perturbs DREAM to promote cellular proliferation and mitotic gene expression. Oncogene 33, 4036–4038.

    Article  CAS  Google Scholar 

  • Eckerdt, F., Perez-Neut, M., and Colamonici, O.R. (2014). LIN-9 phosphorylation on threonine-96 is required for transcriptional activation of LIN-9 target genes and promotes cell cycle progression. PLoS ONE 9, e87620.

    Article  Google Scholar 

  • Filippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W.B., Fedorov, O., Morse, E.M., Keates, T., Hickman, T.T., Felletar, I., et al. (2010). Selective inhibition of BET bromodomains. Nature 468, 1067–1073.

    Article  CAS  Google Scholar 

  • Gagrica, S., Hauser, S., Kolfschoten, I., Osterloh, L., Agami, R., and Gaubatz, S. (2004). Inhibition of oncogenic transformation by mammalian Lin-9, a pRB-associated protein. EMBO J 23, 4627–4638.

    Article  CAS  Google Scholar 

  • Gayle, S.S., Sahni, J.M., and Keri, R.A. (2017). BETi induction of mitotic catastrophe: towing the LIN9. Oncoscience 4, 128–130.

    PubMed  PubMed Central  Google Scholar 

  • Goldspiel, B.R. (1997). Clinical overview of the taxanes. Pharmacotherapy 17, 110S–125S.

    CAS  PubMed  Google Scholar 

  • Hauser, S., Ulrich, T., Wurster, S., Schmitt, K., Reichert, N., and Gaubatz, S. (2012). Loss of LIN9, a member of the DREAM complex, cooperates with SV40 large Tantigen to induce genomic instability and anchorage-independent growth. Oncogene 31, 1859–1868.

    Article  CAS  Google Scholar 

  • Kassam, F., Enright, K., Dent, R., Dranitsaris, G., Myers, J., Flynn, C., Fralick, M., Kumar, R., and Clemons, M. (2009). Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design. Clin Breast Cancer 9, 29–33.

    Article  Google Scholar 

  • Kleinschmidt, M.A., Wagner, T.U., Liedtke, D., Spahr, S., Samans, B., and Gaubatz, S. (2009). lin9 is required for mitosis and cell survival during early zebrafish development. J Biol Chem 284, 13119–13127.

    Article  CAS  Google Scholar 

  • McGrogan, B.T., Gilmartin, B., Carney, D.N., and McCann, A. (2008). Taxanes, microtubules and chemoresistant breast cancer. Biochim Biophys Acta Rev Cancer 1785, 96–132.

    Article  CAS  Google Scholar 

  • Nurse, P. (1990). Universal control mechanism regulating onset of M-phase. Nature 344, 503–508.

    Article  CAS  Google Scholar 

  • Osterloh, L., von Eyss, B., Schmit, F., Rein, L., Hübner, D., Samans, B., Hauser, S., and Gaubatz, S. (2007). The human synMuv-like protein LIN-9 is required for transcription of G2/M genes and for entry into mitosis. EMBO J 26, 144–157.

    Article  CAS  Google Scholar 

  • Paridaens, R., Biganzoli, L., Bruning, P., Klijn, J.G.M., Gamucci, T., Houston, S., Coleman, R., Schachter, J., Van Vreckem, A., Sylvester, R., et al. (2000). Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organization for Research and Treatment of Cancer Randomized Study with cross-over. J Clin Oncol 18, 724.

    Article  CAS  Google Scholar 

  • Pilkinton, M., Sandoval, R., and Colamonici, O.R. (2007). Mammalian Mip/LIN-9 interacts with either the p107, p130/E2F4 repressor complex or B-Myb in a cell cycle-phase-dependent context distinct from the Drosophila dREAM complex. Oncogene 26, 7535–7543.

    Article  CAS  Google Scholar 

  • Rastelli, F., Biancanelli, S., Falzetta, A., Martignetti, A., Casi, C., Bascioni, R., Giustini, L., and Crispino, S. (2010). Triple-negative breast cancer: current state of the art. Tumori J 96, 875–888.

    Article  Google Scholar 

  • Reichert, N., Wurster, S., Ulrich, T., Schmitt, K., Hauser, S., Probst, L., Götz, R., Ceteci, F., Moll, R., Rapp, U., et al. (2010). Lin9, a subunit of the mammalian DREAM complex, is essential for embryonic development, for survival of adult mice, and for tumor suppression. Mol Cell Biol 30, 2896–2908.

    Article  CAS  Google Scholar 

  • Romond, E.H., Perez, E.A., Bryant, J., Suman, V.J., Geyer, C.E. Jr, Davidson, N.E., Tan-Chiu, E., Martino, S., Paik, S., Kaufman, P.A., et al. (2005). Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353, 1673–1684.

    Article  CAS  Google Scholar 

  • Sahni, J.M., Gayle, S.S., Webb, B.M., Weber-Bonk, K.L., Seachrist, D.D., Singh, S., Sizemore, S.T., Restrepo, N.A., Bebek, G., Scacheri, P.C., et al. (2017). Mitotic vulnerability in triple-negative breast cancer associated with LIN9 is targetable with BET inhibitors. Cancer Res 77, 5395–5408.

    Article  CAS  Google Scholar 

  • Schiff, P.B., Fant, J., and Horwitz, S.B. (1979). Promotion of microtubule assembly in vitro by taxol. Nature 277, 665–667.

    Article  CAS  Google Scholar 

  • Schmit, F., Korenjak, M., Mannefeld, M., Schmitt, K., Franke, C., von Eyss, B., Gagrica, S., Hänel, F., Brehm, A., and Gaubatz, S. (2007). LINC, a human complex that is related to pRB-containing complexes in invertebrates regulates the expression of G2/M genes. Cell Cycle 6, 1903–1913.

    Article  CAS  Google Scholar 

  • Shao, T.F., Zheng, Y.T., Zhao, B., Li, T., Cheng, K.G., and Cai, W.M. (2014). Recombinant expression of different mutant K-ras gene in pancreatic cancer Bxpc-3 cells and its effects on chemotherapy sensitivity. Sci China Life Sci 57, 1011–1017.

    Article  CAS  Google Scholar 

  • Shi, H., Bevier, M., Johansson, R., Enquist-Olsson, K., Henriksson, R., Hemminki, K., Lenner, P., and Försti, A. (2012). Prognostic impact of polymorphisms in the MYBL2 interacting genes in breast cancer. Breast Cancer Res Treat 131, 1039–1047.

    Article  CAS  Google Scholar 

  • Sotiriou, C., and Pusztai, L. (2009). Gene-expression signatures in breast cancer. N Engl J Med 360, 790–800.

    Article  CAS  Google Scholar 

  • Stathis, A., Zucca, E., Bekradda, M., Gomez-Roca, C., Delord, J.P., de La Motte Rouge, T., Uro-Coste, E., de Braud, F., Pelosi, G., and French, C. A. (2016). Clinical response of carcinomas harboring the BRD4-NUT oncoprotein to the targeted bromodomain inhibitor OTX015/MK-8628. Cancer Discov 6, 492–500.

    Article  CAS  Google Scholar 

  • Sudo, T., Nitta, M., Saya, H., and Ueno, N.T. (2004). Dependence of paclitaxel sensitivity on a functional spindle assembly checkpoint. Cancer Res 64, 2502–2508.

    Article  CAS  Google Scholar 

  • Tian, S., Roepman, P., Van–t Veer, L.J., Bernards, R., de Snoo, F., and Glas, A.M. (2010). Biological functions of the genes in the mammaprint breast cancer profile reflect the hallmarks of cancer. Biomark Insights 5, BMI.S6184.

    Article  Google Scholar 

  • Torre, L.A., Bray, F., Siegel, R.L., Ferlay, J., Lortet-Tieulent, J., and Jemal, A. (2015). Global cancer statistics, 2012. CA Cancer J Clin 65, 87–108.

    Article  Google Scholar 

  • Wang, T.H., Wang, H.S., and Soong, Y.K. (2000). Paclitaxel-induced cell death. Cancer 88, 2619–2628.

    Article  CAS  Google Scholar 

  • Wiseman, E.F., Chen, X., Han, N., Webber, A., Ji, Z., Sharrocks, A.D., and Ang, Y.S. (2015). Deregulation of the FOXM1 target gene network and its coregulatory partners in oesophageal adenocarcinoma. Mol Cancer 14, 69.

    Article  Google Scholar 

  • Xiang, J., Wu, B., Zhou, Z., Hu, S., Piao, Y., Zhou, Q., Wang, G., Tang, J., Liu, X., and Shen, Y. (2018). Synthesis and evaluation of a paclitaxel-binding polymeric micelle for efficient breast cancer therapy. Sci China Life Sci 61, 436–447.

    Article  CAS  Google Scholar 

  • Ying, X., Huang, A., Xing, Y., Lan, L., Yi, Z., and He, P. (2017). Lycorine inhibits breast cancer growth and metastasis via inducing apoptosis and blocking Src/FAK-involved pathway. Sci China Life Sci 60, 417–428.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81672622, 81702630) and China Post-doctoral Science Foundation (2018M643331).

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Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, 510120, China

    Hongna Lai, Shunying Li, Qianfeng Shi, Zijie Cai, Yudong Li & Yujie Liu

  2. Breast Tumour Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China

    Hongna Lai, Shunying Li, Qianfeng Shi, Zijie Cai, Yudong Li & Yujie Liu

  3. Division of Vascular Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China

    Rui Wang

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  1. Hongna Lai
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Correspondence to Yudong Li or Yujie Liu.

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Lai, H., Wang, R., Li, S. et al. LIN9 confers paclitaxel resistance in triple negative breast cancer cells by upregulating CCSAP. Sci. China Life Sci. 63, 419–428 (2020). https://doi.org/10.1007/s11427-019-9581-8

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  • DOI: https://doi.org/10.1007/s11427-019-9581-8

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