乳癌為世界上造成女性癌症死亡的主因之一。臨床上對於乳癌患者的治療依據乳癌腫瘤分型而有所不同，其中對雌激素受體(estrogen receptor)陽性，例如: 管狀A型（luminal-A）與管狀B型（luminal-B）的乳癌患者，通常給予如芳香環轉化酶抑制劑(aromatase inhibitors)或選擇性雌激素受體調節物(selective estrogen receptor modulators)的輔助性賀爾蒙療法；然而在這樣的治療之下卻也發現許多乳癌患者產生先天性或後天性的賀爾蒙治療抗藥性，導致較差的治療結果。因此本篇研究希望探討造成賀爾蒙治療所產生抗藥性可能的分子機轉。
在本篇研究中，我們發現相較於雌激素受體陽性的MCF7乳癌細胞，由MCF7分離出雌激素受體陽性（MCF7-derived ER+)，和非雌激素依賴型且同時具有泰莫西芬抗藥性的MCF7-TamC3乳癌細胞中，有較高表現量的人類表皮生長因子受體2（HER2）且在表皮生長因子(EGF)刺激下有較明顯的調控反應。此外，次世代定序的結果顯示，在MCF7與MCF7-TamC3間總共有1,755個基因表現有顯著差異，其中我們發現相較於MCF7，MCF7-TamC3的核蛋白1（NUPR1）基因表現顯著的增加。同時在我們的實驗中也進一步證實了MCF7-TamC3細胞中，核蛋白1的信使核糖核酸(mRNA)與蛋白質確實存在較高表現量。另一方面我們也使用線上大數據資料庫進行分析，發現核蛋白1的高表現量與雌激素受體、人類表皮生長因子受體2皆表達陽性的乳癌患者較差的預後有關聯性。甚至，在臨床乳癌檢體中發現越惡性的腫瘤存在越多的核蛋白1。在本實驗中，相較於含有雌激素，我們將MCF7或MCF7-TamC3培養在不含有雌激素的培養基中（模擬患者以芳香環轉化酶抑制劑治療時體內的情形），接著藉由小分子干擾核糖核酸（siRNA）抑制細胞中核蛋白1，會顯著促進細胞死亡。這樣的結果顯示了高表現量的核蛋白1對雌激素受體陽性乳癌細胞在不含有雌激素的情況下，在維持細胞存活應扮演很重要的角色。在分子機轉研究證實，MCF7與MCF7-TamC3細胞中核蛋白1正向調控人類表皮生長因子受體2、組蛋白去乙醯化酶5 （HDAC5）、存活素（survivin），並抑制p53腫瘤抑制蛋白（p53）進入細胞核中。有趣的是，我們若以小分子干擾核糖核酸抑制組蛋白去乙醯化酶5，降低了核蛋白1的蛋白質表現量，而這樣的結果說明了乳癌細胞中的核蛋白1和組蛋白去乙醯化酶5之間，可能存在正向回饋的調控機制。
綜合上述結果表明了，在雌激素受體與人類表皮生長因子受體2皆陽性乳癌細胞中，高表現量的核蛋白1在促進賀爾蒙治療抗藥性中扮演著重要的角色。因此，在未來的治療方針上，若直接標靶核蛋白1應能讓雌激素受體、人類表皮生長因子受體2皆表達陽性乳癌患者克服賀爾蒙治療所產生抗藥性。

Breast cancer is one of the major causes of cancer death in women worldwide. The treatment of breast cancer varies for different breast cancer subtypes, and among them, hormone therapy [i.e. aromatase inhibitors (AIs) or selective estrogen receptor modulators (SERMs)] is usually used as an adjuvant therapy for patients with estrogen receptor positive (ER+) breast cancer (i.e. luminal-A and luminal-B subtypes). However intrinsic or acquired resistance to hormone therapy is often reported and results in poorer management of patients with ER+ breast cancer. In this study, we aimed to investigate the molecular mechanism underlying the hormone therapy resistance in ER+ breast cancer.
In the current study, we found that the MCF7-derived, ER+, estrogen-independent and tamoxifen-cross-resistant, MCF7-TamC3 cells exhibit higher expression of HER2 and higher sensitivity to EGF as compared to the parental ER+ MCF7 breast cancer cells. Results of the transcriptomic analysis (i.e. mRNAseq) revealed a total of 1,755 differentially expressed genes (DEGs) present in MCF7-TamC3 and among these DEGs, nuclear protein-1 (NUPR1) was the most up-regulated gene in MCF7-TamC3, as compared to MCF7 cells. The upregulation of NUPR1 in MCF7-TamC3 cells was further validated by quantitative real-time PCR and Western blot analysis. Analysis on clinical data available online revealed that high expression levels of NUPR1 correlate with poorer prognosis in patients with ER+/HER2+ breast cancer. Moreover, higher expression levels of NUPR1 was found in breast tumor samples of patients with more advanced clinical grades. Downregulation of NUPR1 by siRNA induced pronounced cell death in MCF7 and MCF7-TamC3 cells cultured under estrogen-deprived conditions (mimicking the conditions of aromatase inhibitions), as compared to those cultured under normal conditions, indicating that overexpression of NUPR1 plays an important role in maintain the survival ER+ breast cancer cells under estrogen-deprivation. Mechanistic analysis revealed that NUPR1 positively regulates the expression of HER2, HDAC5, survivin, and negatively regulates the nuclear translocation of p53, in MCF7 and MCF7-TamC3 cells. Intriguingly, molecular downregulation of HDAC5 by siRNA decreased the protein expression levels of NUPR1, suggesting that a positive feedback loop between NUPR1 and HDAC5 may be existed in breast cancer cells.
In conclusion, these findings indicate that overexpression of NUPR1 plays an important role in promoting hormone therapy resistance in ER+/HER2+ breast cancer cells. Targeting NUPR1 may be a potential strategy for overcoming resistance to hormone therapy in patients with ER+/HER2+ breast cancer in the future.

Agis-Balboa, R. C., Pavelka, Z., Kerimoglu, C., & Fischer, A. (2013). Loss of HDAC5 impairs memory function: implications for Alzheimer's disease. J Alzheimers Dis, 33(1), 35-44. doi:10.3233/jad-2012-121009
Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. (2015). The Lancet, 386(10001), 1341-1352. doi:https://doi.org/10.1016/S0140-6736(15)61074-1
Arpino, G., Green, S. J., Allred, D. C., Lew, D., Martino, S., Osborne, C. K., & Elledge, R. M. (2004). HER-2 Amplification, HER-1 Expression, and Tamoxifen Response in Estrogen Receptor-Positive Metastatic Breast Cancer. Clinical Cancer Research, 10(17), 5670. doi:10.1158/1078-0432.CCR-04-0110
Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A. A., Kim, S., . . . Garraway, L. A. (2012). The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature, 483(7391), 603-607. doi:10.1038/nature11003
Berchuck, A., Kamel, A., Whitaker, R., Kerns, B., Olt, G., Kinney, R., . . . Marks, P. (1990). Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer research, 50(13), 4087-4091.
Blander, G., & Guarente, L. (2004). The Sir2 family of protein deacetylases. Annu Rev Biochem, 73, 417-435. doi:10.1146/annurev.biochem.73.011303.073651
Bolden, J. E., Peart, M. J., & Johnstone, R. W. (2006). Anticancer activities of histone deacetylase inhibitors. Nature Reviews Drug Discovery, 5(9), 769-784. doi:10.1038/nrd2133
Brandt-Rauf, P. W., Pincus, M. R., & Carney, W. P. (1994). The c-<i>erbB</i>-2 Protein in Oncogenesis: Molecular Structure to Molecular Epidemiology. 5(2-3), 313-329. doi:10.1615/CritRevOncog.v5.i2-3.100
Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 68(6), 394-424. doi:10.3322/caac.21492
Burgess, A. W., Cho, H.-S., Eigenbrot, C., Ferguson, K. M., Garrett, T. P. J., Leahy, D. J., . . . Yokoyama, S. (2003). An Open-and-Shut Case? Recent Insights into the Activation of EGF/ErbB Receptors. Molecular Cell, 12(3), 541-552. doi:https://doi.org/10.1016/S1097-2765(03)00350-2
Burstein, H. J. (2005). The distinctive nature of HER2-positive breast cancers. New England Journal of Medicine, 353(16), 1652.
Ceccacci, E., & Minucci, S. (2016). Inhibition of histone deacetylases in cancer therapy: lessons from leukaemia. British Journal of Cancer, 114(6), 605-611. doi:10.1038/bjc.2016.36
Chan, R., Hardy, W. R., Laing, M. A., Hardy, S. E., & Muller, W. J. (2002). The Catalytic Activity of the ErbB-2 Receptor Tyrosine Kinase Is Essential for Embryonic Development. Molecular and Cellular Biology, 22(4), 1073. doi:10.1128/MCB.22.4.1073-1078.2002
Cho, H.-S., & Leahy, D. J. (2002). Structure of the Extracellular Region of HER3 Reveals an Interdomain Tether. Science, 297(5585), 1330. doi:10.1126/science.1074611
Cho, Y., Sloutsky, R., Naegle, K. M., & Cavalli, V. (2013). Injury-induced HDAC5 nuclear export is essential for axon regeneration. Cell, 155(4), 894-908. doi:10.1016/j.cell.2013.10.004
Chumsri, S., Howes, T., Bao, T., Sabnis, G., & Brodie, A. (2011). Aromatase, aromatase inhibitors, and breast cancer. The Journal of Steroid Biochemistry and Molecular Biology, 125(1), 13-22. doi:https://doi.org/10.1016/j.jsbmb.2011.02.001
Clark, D. W., Mitra, A., Fillmore, R. A., Jiang, W. G., Samant, R. S., Fodstad, O., & Shevde, L. A. (2008). NUPR1 interacts with p53, transcriptionally regulates p21 and rescues breast epithelial cells from doxorubicin-induced genotoxic stress. Curr Cancer Drug Targets, 8(5), 421-430. doi:10.2174/156800908785133196
De Marchi, T., Foekens, J. A., Umar, A., & Martens, J. W. M. (2016). Endocrine therapy resistance in estrogen receptor (ER)-positive breast cancer. Drug Discovery Today, 21(7), 1181-1188. doi:https://doi.org/10.1016/j.drudis.2016.05.012
Dokmanovic, M., Clarke, C., & Marks, P. A. (2007). Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res, 5(10), 981-989. doi:10.1158/1541-7786.Mcr-07-0324
Dupont, C., Armant, D. R., & Brenner, C. A. (2009). Epigenetics: definition, mechanisms and clinical perspective. Seminars in reproductive medicine, 27(5), 351-357. doi:10.1055/s-0029-1237423
Early Breast Cancer Trialists' Collaborative, G. (2011). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. The Lancet, 378(9793), 771-784. doi:10.1016/S0140-6736(11)60993-8
Emma, M. R., Iovanna, J. L., Bachvarov, D., Puleio, R., Loria, G. R., Augello, G., . . . Cervello, M. (2016). NUPR1, a new target in liver cancer: implication in controlling cell growth, migration, invasion and sorafenib resistance. Cell Death Dis, 7(6), e2269. doi:10.1038/cddis.2016.175
Encinar, J. A., Mallo, G. V., Mizyrycki, C., Giono, L., Gonzalez-Ros, J. M., Rico, M., . . . Iovanna, J. L. (2001). Human p8 is a HMG-I/Y-like protein with DNA binding activity enhanced by phosphorylation. J Biol Chem, 276(4), 2742-2751. doi:10.1074/jbc.M008594200
Gabos, Z., Sinha, R., Hanson, J., Chauhan, N., Hugh, J., Mackey, J. R., & Abdulkarim, B. (2006). Prognostic significance of human epidermal growth factor receptor positivity for the development of brain metastasis after newly diagnosed breast cancer. Journal of Clinical Oncology, 24(36), 5658-5663.
García-Montero, A. C., Vasseur, S., Giono, L. E., Canepa, E., Moreno, S., Dagorn, J. C., & Iovanna, J. L. (2001). Transforming growth factor beta-1 enhances Smad transcriptional activity through activation of p8 gene expression. The Biochemical journal, 357(Pt 1), 249-253. doi:10.1042/0264-6021:3570249
Gilani, R. A., Kazi, A. A., Shah, P., Schech, A. J., Chumsri, S., Sabnis, G., . . . Brodie, A. H. (2012). The importance of HER2 signaling in the tumor-initiating cell population in aromatase inhibitor-resistant breast cancer. Breast Cancer Research and Treatment, 135(3), 681-692. doi:10.1007/s10549-012-2148-8
Gironella, M., Malicet, C., Cano, C., Sandi, M. J., Hamidi, T., Tauil, R. M. N., . . . Iovanna, J. L. (2009). p8/nupr1 regulates DNA-repair activity after double-strand gamma irradiation-induced DNA damage. Journal of Cellular Physiology, 221(3), 594-602. doi:10.1002/jcp.21889
Gray, S. G., & Ekström, T. J. (2001). The human histone deacetylase family. Experimental cell research, 262(2), 75-83.
Guo, X., Wang, W., Hu, J., Feng, K., Pan, Y., Zhang, L., & Feng, Y. (2012). Lentivirus-Mediated RNAi Knockdown of NUPR1 Inhibits Human Nonsmall Cell Lung Cancer Growth In Vitro and In Vivo. The Anatomical Record, 295(12), 2114-2121. doi:10.1002/ar.22571
Gyorffy, B., Lanczky, A., Eklund, A. C., Denkert, C., Budczies, J., Li, Q., & Szallasi, Z. (2010). An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat, 123(3), 725-731. doi:10.1007/s10549-009-0674-9
Hamidi, T., Algül, H., Cano, C. E., Sandi, M. J., Molejon, M. I., Riemann, M., . . . Iovanna, J. L. (2012). Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis. The Journal of clinical investigation, 122(6), 2092-2103. doi:10.1172/JCI60144
He, P., Liang, J., Shao, T., Guo, Y., Hou, Y., & Li, Y. (2015). HDAC5 promotes colorectal cancer cell proliferation by up-regulating DLL4 expression. Int J Clin Exp Med, 8(4), 6510-6516.
Hoffmeister, A., Ropolo, A., Vasseur, S., Mallo, G. V., Bodeker, H., Ritz-Laser, B., . . . Iovanna, J. L. (2002). The HMG-I/Y-related protein p8 binds to p300 and Pax2 trans-activation domain-interacting protein to regulate the trans-activation activity of the Pax2A and Pax2B transcription factors on the glucagon gene promoter. J Biol Chem, 277(25), 22314-22319. doi:10.1074/jbc.M201657200
Howell, A., Cuzick, J., Baum, M., Buzdar, A., Dowsett, M., Forbes, J. F., . . . Tobias, J. S. (2005). Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet, 365(9453), 60-62. doi:10.1016/s0140-6736(04)17666-6
Hsieh, T.-H., Hsu, C.-Y., Tsai, C.-F., Long, C.-Y., Wu, C.-H., Wu, D.-C., . . . Tsai, E.-M. (2015). HDAC Inhibitors Target HDAC5, Upregulate MicroRNA-125a-5p, and Induce Apoptosis in Breast Cancer Cells. Molecular Therapy, 23(4), 656-666. doi:https://doi.org/10.1038/mt.2014.247
Huang, W. T., Tsai, Y. H., Chen, S. H., Kuo, C. W., Kuo, Y. L., Lee, K. T., . . . Cheung, C. H. A. (2017). HDAC2 and HDAC5 Up-Regulations Modulate Survivin and miR-125a-5p Expressions and Promote Hormone Therapy Resistance in Estrogen Receptor Positive Breast Cancer Cells. Front Pharmacol, 8, 902. doi:10.3389/fphar.2017.00902
Huang, X., Wang, S., Lee, C.-K., Yang, X., & Liu, B. (2011). HDAC inhibitor SNDX-275 enhances efficacy of trastuzumab in erbB2-overexpressing breast cancer cells and exhibits potential to overcome trastuzumab resistance. Cancer Letters, 307(1), 72-79. doi:https://doi.org/10.1016/j.canlet.2011.03.019
Hurtado, A., Holmes, K. A., Geistlinger, T. R., Hutcheson, I. R., Nicholson, R. I., Brown, M., . . . Carroll, J. S. (2008). Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen. Nature, 456(7222), 663-666. doi:10.1038/nature07483
Iqbal, N., & Iqbal, N. (2014). Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Molecular Biology International, 2014, 852748. doi:10.1155/2014/852748
Ito, Y., Yoshida, H., Motoo, Y., Iovanna, J. L., Tomoda, C., Uruno, T., . . . Miyauchi, A. (2005). Expression of p8 protein in medullary thyroid carcinoma. Anticancer Res, 25(5), 3419-3423.
Jia, Q., Zhou, W., Yao, W., Yang, F., Zhang, S., Singh, R., . . . Wang, N. (2016). Downregulation of YAP-dependent Nupr1 promotes tumor-repopulating cell growth in soft matrices. Oncogenesis, 5(4), e220-e220. doi:10.1038/oncsis.2016.29
Jung, S.-H., Lee, A., Yim, S.-H., Hu, H.-J., Choe, C., & Chung, Y.-J. (2012). Simultaneous copy number gains of NUPR1 and ERBB2 predicting poor prognosis in early-stage breast cancer. BMC cancer, 12, 382-382. doi:10.1186/1471-2407-12-382
Kallwellis, K., Grempler, R., Günther, S., Päth, G., & Walther, R. (2006). Tumor necrosis factor alpha induces the expression of the nuclear protein p8 via a novel NF kappaB binding site within the promoter. Horm Metab Res, 38(9), 570-574. doi:10.1055/s-2006-950503
Kim, D., Langmead, B., & Salzberg, S. L. (2015). HISAT: a fast spliced aligner with low memory requirements. Nature Methods, 12(4), 357-360. doi:10.1038/nmeth.3317
Kong, D. K., Georgescu, S. P., Cano, C., Aronovitz, M. J., Iovanna, J. L., Patten, R. D., . . . Goruppi, S. (2010). Deficiency of the transcriptional regulator p8 results in increased autophagy and apoptosis, and causes impaired heart function. Mol Biol Cell, 21(8), 1335-1349. doi:10.1091/mbc.E09-09-0818
Krusche, C. A., Wulfing, P., Kersting, C., Vloet, A., Bocker, W., Kiesel, L., . . . Alfer, J. (2005). Histone deacetylase-1 and -3 protein expression in human breast cancer: a tissue microarray analysis. Breast Cancer Res Treat, 90(1), 15-23. doi:10.1007/s10549-004-1668-2
Kuo, C.-N., Liao, Y.-M., Kuo, L.-N., Tsai, H.-J., Chang, W.-C., & Yen, Y. (2019). Cancers in Taiwan: Practical insight from epidemiology, treatments, biomarkers, and cost. Journal of the Formosan Medical Association. doi:https://doi.org/10.1016/j.jfma.2019.08.023
Lee, J., Kuo, C.-W., Tsai, S.-L., Cheng, S. M., Chen, S.-H., Chan, H.-H., . . . Cheung, C. H. (2016). Inhibition of HDAC3- and HDAC6-Promoted Survivin Expression Plays an Important Role in SAHA-Induced Autophagy and Viability Reduction in Breast Cancer Cells. Frontiers in Pharmacology, 7. doi:10.3389/fphar.2016.00081
Lemmon, M. A., & Schlessinger, J. (2010). Cell Signaling by Receptor Tyrosine Kinases. Cell, 141(7), 1117-1134. doi:https://doi.org/10.1016/j.cell.2010.06.011
Leong, S. P., Shen, Z. Z., Liu, T. J., Agarwal, G., Tajima, T., Paik, N. S., . . . Foulkes, W. D. (2010). Is breast cancer the same disease in Asian and Western countries? World J Surg, 34(10), 2308-2324. doi:10.1007/s00268-010-0683-1
Li, J., Ren, S., Liu, Y., Lian, Z., Dong, B., Yao, Y., & Xu, Y. (2017). Knockdown of NUPR1 inhibits the proliferation of glioblastoma cells via ERK1/2, p38 MAPK and caspase-3. J Neurooncol, 132(1), 15-26. doi:10.1007/s11060-016-2337-0
Lin, T. Y., Chan, H. H., Chen, S. H., Sarvagalla, S., Chen, P. S., Coumar, M. S., . . . Cheung, C. H. A. (2019). BIRC5/Survivin is a novel ATG12-ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells. Autophagy, 1-18. doi:10.1080/15548627.2019.1671643
Ma, C. X., Reinert, T., Chmielewska, I., & Ellis, M. J. (2015). Mechanisms of aromatase inhibitor resistance. Nature Reviews Cancer, 15(5), 261-275. doi:10.1038/nrc3920
Malicet, C., Giroux, V., Vasseur, S., Dagorn, J. C., Neira, J. L., & Iovanna, J. L. (2006). Regulation of apoptosis by the p8/prothymosin alpha complex. Proceedings of the National Academy of Sciences of the United States of America, 103(8), 2671-2676. doi:10.1073/pnas.0508955103
Malicet, C., Hoffmeister, A., Moreno, S., Closa, D., Dagorn, J. C., Vasseur, S., & Iovanna, J. L. (2006). Interaction of the stress protein p8 with Jab1 is required for Jab1-dependent p27 nuclear-to-cytoplasm translocation. Biochem Biophys Res Commun, 339(1), 284-289. doi:10.1016/j.bbrc.2005.11.018
Marks, P., Rifkind, R. A., Richon, V. M., Breslow, R., Miller, T., & Kelly, W. K. (2001). Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer, 1(3), 194-202. doi:10.1038/35106079
Massarweh, S., Osborne, C. K., Creighton, C. J., Qin, L., Tsimelzon, A., Huang, S., . . . Schiff, R. (2008). Tamoxifen Resistance in Breast Tumors Is Driven by Growth Factor Receptor Signaling with Repression of Classic Estrogen Receptor Genomic Function. Cancer Research, 68(3), 826. doi:10.1158/0008-5472.CAN-07-2707
Mi, H., Muruganujan, A., Casagrande, J. T., & Thomas, P. D. (2013). Large-scale gene function analysis with the PANTHER classification system. Nat Protoc, 8(8), 1551-1566. doi:10.1038/nprot.2013.092
Miller, W. R. (2003). Aromatase inhibitors: mechanism of action and role in the treatment of breast cancer. Semin Oncol, 30(4 Suppl 14), 3-11. doi:10.1016/s0093-7754(03)00302-6
Mita, A. C., Mita, M. M., Nawrocki, S. T., & Giles, F. J. (2008). Survivin: Key Regulator of Mitosis and Apoptosis and Novel Target for Cancer Therapeutics. Clinical Cancer Research, 14(16), 5000. doi:10.1158/1078-0432.CCR-08-0746
Miyake, K., Yoshizumi, T., Imura, S., Sugimoto, K., Batmunkh, E., Kanemura, H., . . . Shimada, M. (2008). Expression of hypoxia-inducible factor-1alpha, histone deacetylase 1, and metastasis-associated protein 1 in pancreatic carcinoma: correlation with poor prognosis with possible regulation. Pancreas, 36(3), e1-9. doi:10.1097/MPA.0b013e31815f2c2a
Moasser, M. M. (2007). The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene, 26(45), 6469-6487. doi:10.1038/sj.onc.1210477
Nahta, R., Yuan, L. X. H., Zhang, B., Kobayashi, R., & Esteva, F. J. (2005). Insulin-like Growth Factor-I Receptor/Human Epidermal Growth Factor Receptor 2 Heterodimerization Contributes to Trastuzumab Resistance of Breast Cancer Cells. Cancer Research, 65(23), 11118. doi:10.1158/0008-5472.CAN-04-3841
Oltra, S. S., Cejalvo, J. M., Tormo, E., Albanell, M., Ferrer, A., Nacher, M., . . . Martinez, M. T. (2020). HDAC5 Inhibitors as a Potential Treatment in Breast Cancer Affecting Very Young Women. Cancers, 12(2), 412. doi:10.3390/cancers12020412
Osada, H., Tatematsu, Y., Saito, H., Yatabe, Y., Mitsudomi, T., & Takahashi, T. (2004). Reduced expression of class II histone deacetylase genes is associated with poor prognosis in lung cancer patients. Int J Cancer, 112(1), 26-32. doi:10.1002/ijc.20395
Osborne, C. K. (1998). Tamoxifen in the Treatment of Breast Cancer. New England Journal of Medicine, 339(22), 1609-1618. doi:10.1056/nejm199811263392207
Ozdağ, H., Teschendorff, A. E., Ahmed, A. A., Hyland, S. J., Blenkiron, C., Bobrow, L., . . . Caldas, C. (2006). Differential expression of selected histone modifier genes in human solid cancers. BMC Genomics, 7, 90. doi:10.1186/1471-2164-7-90
Ree, A. H., Pacheco, M. M., Tvermyr, M., Fodstad, O., & Brentani, M. M. (2000). Expression of a novel factor, com1, in early tumor progression of breast cancer. Clin Cancer Res, 6(5), 1778-1783.
Rhodes, D. R., Yu, J., Shanker, K., Deshpande, N., Varambally, R., Ghosh, D., . . . Chinnaiyan, A. M. (2004). ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia (New York, N.Y.), 6(1), 1-6. doi:10.1016/s1476-5586(04)80047-2
Ropero, S., & Esteller, M. (2007). The role of histone deacetylases (HDACs) in human cancer. Molecular Oncology, 1(1), 19-25. doi:https://doi.org/10.1016/j.molonc.2007.01.001
Roy, V., & Perez, E. A. (2009). Beyond Trastuzumab: Small Molecule Tyrosine Kinase Inhibitors in HER-2–Positive Breast Cancer. The Oncologist, 14(11), 1061-1069. doi:10.1634/theoncologist.2009-0142
Santin, A. D., Bellone, S., Van Stedum, S., Bushen, W., Palmieri, M., Siegel, E. R., . . . Pecorelli, S. (2005). Amplification of c‐erbB2 oncogene: a major prognostic indicator in uterine serous papillary carcinoma. Cancer, 104(7), 1391-1397.
Schulze, W. X., Deng, L., & Mann, M. (2005). Phosphotyrosine interactome of the ErbB-receptor kinase family. Molecular Systems Biology, 1(1), 2005.0008. doi:10.1038/msb4100012
Scott, G. K., Marden, C., Xu, F., Kirk, L., & Benz, C. C. (2002). Transcriptional repression of ErbB2 by histone deacetylase inhibitors detected by a genomically integrated ErbB2 promoter-reporting cell screen. Mol Cancer Ther, 1(6), 385-392.
Shin, S., Sung, B. J., Cho, Y. S., Kim, H. J., Ha, N. C., Hwang, J. I., . . . Oh, B. H. (2001). An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. Biochemistry, 40(4), 1117-1123. doi:10.1021/bi001603q
Shiraki, M., Xu, X., Iovanna, J. L., Kukita, T., Hirata, H., Kamohara, A., . . . Kukita, A. (2019). Deficiency of stress-associated gene Nupr1 increases bone volume by attenuating differentiation of osteoclasts and enhancing differentiation of osteoblasts. The FASEB Journal, 33(8), 8836-8852. doi:10.1096/fj.201802322RR
Shou, J., Massarweh, S., Osborne, C. K., Wakeling, A. E., Ali, S., Weiss, H., & Schiff, R. (2004). Mechanisms of Tamoxifen Resistance: Increased Estrogen Receptor-HER2/neu Cross-Talk in ER/HER2–Positive Breast Cancer. JNCI: Journal of the National Cancer Institute, 96(12), 926-935. doi:10.1093/jnci/djh166
Silke, J., & Meier, P. (2013). Inhibitor of apoptosis (IAP) proteins-modulators of cell death and inflammation. Cold Spring Harbor perspectives in biology, 5(2), a008730. doi:10.1101/cshperspect.a008730
Slamon, D. J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A., & McGuire, W. L. (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. science, 235(4785), 177-182.
Spizzo, R., Almeida, M. I., Colombatti, A., & Calin, G. A. (2012). Long non-coding RNAs and cancer: a new frontier of translational research? Oncogene, 31(43), 4577-4587. doi:10.1038/onc.2011.621
Sun, C., Reimers, L. L., & Burk, R. D. (2011). Methylation of HPV16 genome CpG sites is associated with cervix precancer and cancer. Gynecologic oncology, 121(1), 59-63. doi:10.1016/j.ygyno.2011.01.013
Taïeb, D., Malicet, C., Garcia, S., Rocchi, P., Arnaud, C., Dagorn, J. C., . . . Vasseur, S. (2005). Inactivation of stress protein p8 increases murine carbon tetrachloride hepatotoxicity via preserved CYP2E1 activity. Hepatology, 42(1), 176-182. doi:10.1002/hep.20759
Tamm, I., Wang, Y., Sausville, E., Scudiero, D. A., Vigna, N., Oltersdorf, T., & Reed, J. C. (1998). IAP-Family Protein Survivin Inhibits Caspase Activity and Apoptosis Induced by Fas (CD95), Bax, Caspases, and Anticancer Drugs. Cancer Research, 58(23), 5315. Retrieved from http://cancerres.aacrjournals.org/content/58/23/5315.abstract
Tang, Z., Li, C., Kang, B., Gao, G., Li, C., & Zhang, Z. (2017). GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res, 45(W1), W98-w102. doi:10.1093/nar/gkx247
Trapnell, C., Roberts, A., Goff, L., Pertea, G., Kim, D., Kelley, D. R., . . . Pachter, L. (2012). Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nature protocols, 7(3), 562-578. doi:10.1038/nprot.2012.016
Vasseur, S., Hoffmeister, A., Garcia-Montero, A., Mallo, G. V., Feil, R., Kuhbandner, S., . . . Iovanna, J. L. (2002). p8-deficient fibroblasts grow more rapidly and are more resistant to adriamycin-induced apoptosis. Oncogene, 21(11), 1685-1694. doi:10.1038/sj.onc.1205222
Vigushin, D. M., Ali, S., Pace, P. E., Mirsaidi, N., Ito, K., Adcock, I., & Coombes, R. C. (2001). Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. Clinical Cancer Research, 7(4), 971-976.
Waks, A. G., & Winer, E. P. (2019). Breast Cancer Treatment: A Review. JAMA, 321(3), 288-300. doi:10.1001/jama.2018.19323
Weichert, W., Röske, A., Niesporek, S., Noske, A., Buckendahl, A.-C., Dietel, M., . . . Denkert, C. (2008). Class I Histone Deacetylase Expression Has Independent Prognostic Impact in Human Colorectal Cancer: Specific Role of Class I Histone Deacetylases <em>In vitro</em> and <em>In vivo</em>. Clinical Cancer Research, 14(6), 1669. doi:10.1158/1078-0432.CCR-07-0990
Xue, Y., Lian, W., Zhi, J., Yang, W., Li, Q., Guo, X., . . . Wang, Q. (2019). HDAC5-mediated deacetylation and nuclear localisation of SOX9 is critical for tamoxifen resistance in breast cancer. British Journal of Cancer, 121(12), 1039-1049. doi:10.1038/s41416-019-0625-0
Yonemura, Y., Ninomiya, I., Yamaguchi, A., Fushida, S., Kimura, H., Ohoyama, S., . . . Sasaki, T. (1991). Evaluation of immunoreactivity for erbB-2 protein as a marker of poor short term prognosis in gastric cancer. Cancer research, 51(3), 1034-1038.
Yu, G., Wang, L. G., Han, Y., & He, Q. Y. (2012). clusterProfiler: an R package for comparing biological themes among gene clusters. Omics, 16(5), 284-287. doi:10.1089/omi.2011.0118
Zeng, C., Li, X., Li, A., Yi, B., Peng, X., Huang, X., & Chen, J. (2018). Knockdown of NUPR1 inhibits the growth of U266 and RPMI8226 multiple myeloma cell lines via activating PTEN and caspase activationdependent apoptosis. Oncol Rep, 40(3), 1487-1494. doi:10.3892/or.2018.6544
Zhan, N., Dong, W.-G., Tang, Y.-F., Wang, Z.-S., & Xiong, C.-l. (2012). Analysis of HER2 gene amplification and protein expression in esophageal squamous cell carcinoma. Medical oncology, 29(2), 933-940.
Zhang, C. L., McKinsey, T. A., Chang, S., Antos, C. L., Hill, J. A., & Olson, E. N. (2002). Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell, 110(4), 479-488. doi:10.1016/s0092-8674(02)00861-9
Zhong, L., Sun, S., Yao, S., Han, X., Gu, M., & Shi, J. (2018). Histone deacetylase 5 promotes the proliferation and invasion of lung cancer cells. Oncol Rep, 40(4), 2224-2232. doi:10.3892/or.2018.6591
Zinke, I., Schütz, C. S., Katzenberger, J. D., Bauer, M., & Pankratz, M. J. (2002). Nutrient control of gene expression in Drosophila: microarray analysis of starvation and sugar-dependent response. Embo j, 21(22), 6162-6173. doi:10.1093/emboj/cdf600