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FBXL2 promotes E47 protein instability to inhibit breast cancer stemness and paclitaxel resistance

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high risk of metastasis and recurrence. Although chemotherapy has greatly improved the clinical outcome of TNBC patients, acquired drug resistance remains a huge challenge for TNBC treatment. Breast cancer stem cells (BCSCs) play a critical role in breast cancer development, metastasis, recurrence, and chemotherapy resistance. Thus, it is of great importance to decipher the underlying molecular mechanism of BCSCs regulation for TNBC drug resistance. In this study, we demonstrate that the F-box protein FBXL2 is a critical negative regulator of BCSCs stemness and that downregulation of FBXL2 plays a causal role in TNBC drug resistance. We show that expression levels of FBXL2 significantly influence CD44high/CD24low subpopulation and the mammosphere formation ability of TNBC cells. Ectopic expression of FBXL2 inhibits initiation of TNBC and overcomes paclitaxel resistance in vivo. In addition, activation of FBXL2 by nebivolol, a clinically used small-molecule inhibitor of the beta-1 receptor, markedly overcomes BCSCs-induced paclitaxel resistance. Mechanistically, we show that FBXL2 targets transcriptional factor E47 for polyubiquitin- and proteasome-mediated degradation, resulting in inhibition of BCSC stemness. Clinical analyses indicate that low expression of FBXL2 correlates with high expression of E47 as well as with high stemness features, and is associated with poor clinical outcomes of breast cancer patients. Taken together, these results highlight that the FBXL2-E47 axis plays a critical role in the regulation of BCSC stemness and paclitaxel resistance. Thus, targeting FBXL2 might be a potential therapeutic strategy for drug-resistant TNBC.

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Fig. 1: Reduced FBXL2 expression correlates with BCSCs marker CD44/CD24 expression and is associated with poor clinical outcomes of breast cancer patients.
Fig. 2: FBXL2 inhibits stemness and tumor initiation ability of BCSCs.
Fig. 3: FBXL2 binds to and targets E47 protein for proteasomal degradation to inhibit stemness of breast cancer cells.
Fig. 4: Inhibition of FBXL2 expression critically contributes to paclitaxel (PTX) resistance of TNBC in vivo.
Fig. 5: Activation of FBXL2 by nebivolol inhibits paclitaxel resistance of TNBC.

Data availability

All data supporting the findings of this study are available from the corresponding authors upon reasonable request. The public datasets used to bioinformatic analyses are available in supplementary tables (Supplementary Tables S1S3).

References

  1. Wang C, Kar S, Lai X, Cai W, Arfuso F, Sethi G, et al. Triple negative breast cancer in Asia: An insider’s view. Cancer Treat Rev. 2018;62:29–38.

    Article  Google Scholar 

  2. Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol. 2006;19:264–71.

    Article  CAS  Google Scholar 

  3. Aysola K, Desai A, Welch C, Xu J, Qin Y, Reddy V, et al. Triple negative breast cancer - an overview. Hereditary Genet. 2013;2013:001.

  4. Gradishar WJ, Moran MS, Abraham J, NCCN Clinical Practice Guidelines in Oncology Breast Cancer (Version 4.2022). 2022: NCCN. Available from https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf

  5. Ren XY, Song Y, Wang J, Chen LY, Pang JY, Zhou LR, et al. Mismatch repair deficiency and microsatellite instability in triple-negative breast cancer: a retrospective study of 440 patients. Front Oncol. 2021;11:570623.

    Article  Google Scholar 

  6. King TD, Suto MJ, Li Y. The Wnt/beta-catenin signaling pathway: a potential therapeutic target in the treatment of triple negative breast cancer. J Cell Biochem. 2012;113:13–8.

    Article  CAS  Google Scholar 

  7. Habib JG, O’Shaughnessy JA. The hedgehog pathway in triple-negative breast cancer. Cancer Med. 2016;5:2989–3006.

    Article  Google Scholar 

  8. Giuli MV, Giuliani E, Screpanti I, Bellavia D, Checquolo S. Notch signaling activation as a hallmark for triple-negative breast cancer subtype. J Oncol. 2019;2019:8707053.

    Article  CAS  Google Scholar 

  9. Zhao L, Qiu T, Jiang D, Xu H, Zou L, Yang Q, et al. SGCE promotes breast cancer stem cells by stabilizing EGFR. Adv Sci (Weinh). 2020;7:1903700.

    Article  CAS  Google Scholar 

  10. Ehmsen S, Ditzel HJ. Signaling pathways essential for triple-negative breast cancer stem-like cells. Stem Cells. 2021;39:133–43.

    Article  CAS  Google Scholar 

  11. Liu S, Wicha MS. Targeting breast cancer stem cells. J Clin Oncol. 2010;28:4006–12.

    Article  CAS  Google Scholar 

  12. Wu, HJ and PY Chu. Epigenetic regulation of breast cancer stem cells contributing to carcinogenesis and therapeutic implications. Int J Mol Sci. 2021;22:8113.

  13. Liu S, Cong Y, Wang D, Sun Y, Deng L, Liu Y, et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep. 2014;2:78–91.

    Article  CAS  Google Scholar 

  14. Ye X, Tam WL, Shibue T, Kaygusuz Y, Reinhardt F, Ng Eaton E, et al. Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature. 2015;525:256–60.

    Article  CAS  Google Scholar 

  15. Wang Y, Shi J, Chai K, Ying X, Zhou BP. The role of snail in EMT and tumorigenesis. Curr Cancer Drug Targets. 2013;13:963–72.

    Article  CAS  Google Scholar 

  16. Shih JY, Yang PC. The EMT regulator slug and lung carcinogenesis. Carcinogenesis. 2011;32:1299–304.

    Article  CAS  Google Scholar 

  17. Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A, et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol. 2009;11:1487–95.

    Article  CAS  Google Scholar 

  18. Meng J, Chen S, Han JX, Qian B, Wang XR, Zhong WL, et al. Twist1 regulates vimentin through Cul2 circular RNA to promote EMT in hepatocellular carcinoma. Cancer Res. 2018;78:4150–62.

    Article  CAS  Google Scholar 

  19. Liang Y, Hu J, Li J, Liu Y, Yu J, Zhuang X, et al. Epigenetic activation of TWIST1 by MTDH promotes cancer stem-like cell traits in breast cancer. Cancer Res. 2015;75:3672–80.

    Article  CAS  Google Scholar 

  20. Lopez-Menendez C, Vazquez-Naharro A, Santos V, Dubus P, Santamaria PG, Martinez-Ramirez A, et al. E2A modulates stemness, metastasis, and therapeutic resistance of breast cancer. Cancer Res. 2021;81:4529–44.

    Article  CAS  Google Scholar 

  21. Lehmann W, Mossmann D, Kleemann J, Mock K, Meisinger C, Brummer T, et al. ZEB1 turns into a transcriptional activator by interacting with YAP1 in aggressive cancer types. Nat Commun. 2016;7:10498.

    Article  CAS  Google Scholar 

  22. Vesuna F, Lisok A, Kimble B, Raman V. Twist modulates breast cancer stem cells by transcriptional regulation of CD24 expression. Neoplasia. 2009;11:1318–28.

    Article  CAS  Google Scholar 

  23. Murre C, McCaw PS, Baltimore D. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell. 1989;56:777–83.

    Article  CAS  Google Scholar 

  24. Bain G. Both E12 and E47 allow commitment to the B cell lineage. Immunity. 1997;6:145–54.

  25. Perez-Moreno MA, Locascio A, Rodrigo I, Dhondt G, Portillo F, Nieto MA, et al. A new role for E12/E47 in the repression of E-cadherin expression and epithelial-mesenchymal transitions. J Biol Chem. 2001;276:27424–31.

    Article  CAS  Google Scholar 

  26. Schwartz R, Engel I, Fallahi-Sichani M, Petrie HT, Murre C. Gene expression patterns define novel roles for E47 in cell cycle progression, cytokine-mediated signaling, and T lineage development. Proc Natl Acad Sci USA. 2006;103:9976–81.

    Article  CAS  Google Scholar 

  27. Xu J, Li F, Gao Y, Guo R, Ding L, Fu M, et al. E47 upregulates DeltaNp63alpha to promote growth of squamous cell carcinoma. Cell Death Dis. 2021;12:381.

    Article  CAS  Google Scholar 

  28. Hayashi M, Nimura K, Kashiwagi K, Harada T, Takaoka K, Kato H, et al. Comparative roles of Twist-1 and Id1 in transcriptional regulation by BMP signaling. J Cell Sci. 2007;120:1350–7.

    Article  CAS  Google Scholar 

  29. Chang AT, Liu Y, Ayyanathan K, Benner C, Jiang Y, Prokop JW, et al. An evolutionarily conserved DNA architecture determines target specificity of the TWIST family bHLH transcription factors. Genes Dev. 2015;29:603–16.

    Article  CAS  Google Scholar 

  30. Hwang-Verslues WW, Chang PH, Wei PC, Yang CY, Huang CK, Kuo WH, et al. miR-495 is upregulated by E12/E47 in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance via downregulation of E-cadherin and REDD1. Oncogene. 2011;30:2463–74.

    Article  CAS  Google Scholar 

  31. Nie L, Wu H, Sun XH. Ubiquitination and degradation of Tal1/SCL are induced by notch signaling and depend on Skp2 and CHIP. J Biol Chem. 2008;283:684–92.

    Article  CAS  Google Scholar 

  32. Gui T, Liu M, Yao B, Jiang H, Yang D, Li Q, et al. TCF3 is epigenetically silenced by EZH2 and DNMT3B and functions as a tumor suppressor in endometrial cancer. Cell Death Differ. 2021;28:3316–28.

    Article  CAS  Google Scholar 

  33. Chen BB, Glasser JR, Coon TA, Mallampalli RK. Skp-cullin-F box E3 ligase component FBXL2 ubiquitinates Aurora B to inhibit tumorigenesis. Cell Death Dis. 2013;4:e759.

    Article  CAS  Google Scholar 

  34. Chen BB, Glasser JR, Coon TA, Mallampalli RK. F-box protein FBXL2 exerts human lung tumor suppressor-like activity by ubiquitin-mediated degradation of cyclin D3 resulting in cell cycle arrest. Oncogene. 2012;31:2566–79.

    Article  CAS  Google Scholar 

  35. Chen BB, Glasser JR, Coon TA, Zou C, Miller HL, Fenton M, et al. F-box protein FBXL2 targets cyclin D2 for ubiquitination and degradation to inhibit leukemic cell proliferation. Blood. 2012;119:3132–41.

    Article  CAS  Google Scholar 

  36. Chen BB, Coon TA, Glasser JR, McVerry BJ, Zhao J, Zhao Y, et al. A combinatorial F box protein directed pathway controls TRAF adaptor stability to regulate inflammation. Nat Immunol. 2013;14:470–9.

    Article  CAS  Google Scholar 

  37. Niu M, Xu J, Liu Y, Li Y, He T, Ding L, et al. FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth. Nat Commun. 2021;12:5919.

    Article  CAS  Google Scholar 

  38. Tekcham DS, Chen D, Liu Y, Ling T, Zhang Y, Chen H, et al. F-box proteins and cancer: an update from functional and regulatory mechanism to therapeutic clinical prospects. Theranostics. 2020;10:4150–67.

    Article  CAS  Google Scholar 

  39. Ginestier C, Cervera N, Finetti P, Esteyries S, Esterni B, Adelaide J, et al. Prognosis and gene expression profiling of 20q13-amplified breast cancers. Clin Cancer Res. 2006;12:4533–44.

    Article  CAS  Google Scholar 

  40. Muto Y, Nishiyama M, Nita A, Moroishi T, Nakayama KI. Essential role of FBXL5-mediated cellular iron homeostasis in maintenance of hematopoietic stem cells. Nat Commun. 2017;8:16114.

    Article  CAS  Google Scholar 

  41. Zhang P, Lathia JD, Flavahan WA, Rich JN, Mattson MP. Squelching glioblastoma stem cells by targeting REST for proteasomal degradation. Trends Neurosci. 2009;32:559–65.

    Article  CAS  Google Scholar 

  42. Vaidyanathan S, Cato K, Tang L, Pavey S, Haass NK, Gabrielli BG, et al. In vivo overexpression of Emi1 promotes chromosome instability and tumorigenesis. Oncogene. 2016;35:5446–55.

    Article  CAS  Google Scholar 

  43. Li Y, Maleki M, Carruthers NJ, Stemmer PM, Ngom A, Rueda L. The predictive performance of short-linear motif features in the prediction of calmodulin-binding proteins. BMC Bioinforma. 2018;19:410.

    Article  CAS  Google Scholar 

  44. Yap KL, Kim J, Truong K, Sherman M, Yuan T, Ikura M. Calmodulin target database. J Struct Funct Genomics. 2000;1:8–14.

    Article  CAS  Google Scholar 

  45. Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y, Albu M, et al. The human transcription factors. Cell. 2018;172:650–65.

    Article  CAS  Google Scholar 

  46. Boisson B, Wang YD, Bosompem A, Ma CS, Lim A, Kochetkov T, et al. A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells. J Clin Invest. 2013;123:4781–5.

    Article  CAS  Google Scholar 

  47. Bhola NE, Balko JM, Dugger TC, Kuba MG, Sanchez V, Sanders M, et al. TGF-beta inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest. 2013;123:1348–58.

    Article  CAS  Google Scholar 

  48. Kawiak A, Domachowska A, Lojkowska E. Plumbagin increases paclitaxel-induced cell death and overcomes paclitaxel resistance in breast cancer cells through ERK-mediated apoptosis induction. J Nat Prod. 2019;82:878–85.

    Article  CAS  Google Scholar 

  49. Ajabnoor GM, Crook T, Coley HM. Paclitaxel resistance is associated with switch from apoptotic to autophagic cell death in MCF-7 breast cancer cells. Cell Death Dis. 2012;3:e260.

    Article  CAS  Google Scholar 

  50. Khan AQ, Al-Tamimi M, Uddin S, Steinhoff M. F-box proteins in cancer stemness: An emerging prognostic and therapeutic target. Drug Disco Today. 2021;26:2905–14.

    Article  CAS  Google Scholar 

  51. Chan CH, Morrow JK, Li CF, Gao Y, Jin G, Moten A, et al. Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression. Cell. 2013;154:556–68.

    Article  CAS  Google Scholar 

  52. Wang Y, Liu Y, Lu J, Zhang P, Wang Y, Xu Y, et al. Rapamycin inhibits FBXW7 loss-induced epithelial-mesenchymal transition and cancer stem cell-like characteristics in colorectal cancer cells. Biochem Biophys Res Commun. 2013;434:352–6.

    Article  CAS  Google Scholar 

  53. Matsuoka S, Oike Y, Onoyama I, Iwama A, Arai F, Takubo K, et al. Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL. Genes Dev. 2008;22:986–91.

    Article  CAS  Google Scholar 

  54. Rustighi A, Zannini A, Tiberi L, Sommaggio R, Piazza S, Sorrentino G, et al. Prolyl-isomerase Pin1 controls normal and cancer stem cells of the breast. EMBO Mol Med. 2014;6:99–119.

    Article  CAS  Google Scholar 

  55. Ma SY, Park JH, Jung H, Ha SM, Kim Y, Park DH, et al. Snail maintains metastatic potential, cancer stem-like properties, and chemoresistance in mesenchymal mouse breast cancer TUBOP2J cells. Oncol Rep. 2017;38:1867–76.

    Article  CAS  Google Scholar 

  56. Storci G, Sansone P, Mari S, D’Uva G, Tavolari S, Guarnieri T, et al. TNFalpha up-regulates SLUG via the NF-kappaB/HIF1alpha axis, which imparts breast cancer cells with a stem cell-like phenotype. J Cell Physiol. 2010;225:682–91.

    Article  CAS  Google Scholar 

  57. Zhang Y, Xu L, Li A, Han X. The roles of ZEB1 in tumorigenic progression and epigenetic modifications. Biomed Pharmacother. 2019;110:400–8.

    Article  CAS  Google Scholar 

  58. Jiang S, Zhang M, Zhang Y, Zhou W, Zhu T, Ruan Q, et al. WNT5B governs the phenotype of basal-like breast cancer by activating WNT signaling. Cell Commun Signal. 2019;17:109.

    Article  Google Scholar 

  59. Zhou L, Wang D, Sheng D, Xu J, Chen W, Qin Y, et al. NOTCH4 maintains quiescent mesenchymal-like breast cancer stem cells via transcriptionally activating SLUG and GAS1 in triple-negative breast cancer. Theranostics. 2020;10:2405–21.

    Article  CAS  Google Scholar 

  60. Cho Y, Lee HW, Kang HG, Kim HY, Kim SJ, Chun KH. Cleaved CD44 intracellular domain supports activation of stemness factors and promotes tumorigenesis of breast cancer. Oncotarget. 2015;6:8709–21.

    Article  Google Scholar 

  61. Yin J, Zheng G, Jia X, Zhang Z, Zhang W, Song Y, et al. A Bmi1-miRNAs cross-talk modulates chemotherapy response to 5-fluorouracil in breast cancer cells. PLoS One. 2013;8:e73268.

    Article  CAS  Google Scholar 

  62. Oku Y, Nishiya N, Shito T, Yamamoto R, Yamamoto Y, Oyama C, et al. Small molecules inhibiting the nuclear localization of YAP/TAZ for chemotherapeutics and chemosensitizers against breast cancers. FEBS Open Bio. 2015;5:542–9.

    Article  CAS  Google Scholar 

  63. Weaver BA. How Taxol/paclitaxel kills cancer cells. Mol Biol Cell. 2014;25:2677–81.

    Article  Google Scholar 

  64. Duan Z, Lamendola DE, Penson RT, Kronish KM, Seiden MV. Overexpression of IL-6 but not IL-8 increases paclitaxel resistance of U-2OS human osteosarcoma cells. Cytokine. 2002;17:234–42.

    Article  CAS  Google Scholar 

  65. Sharma N, Ramachandran S, Bowers M, Yegappan M, Brown R, Aziz S, et al. Multiple factors other than p53 influence colon cancer sensitivity to paclitaxel. Cancer Chemother Pharm. 2000;46:329–37.

    Article  CAS  Google Scholar 

  66. Giannakakou P, Sackett DL, Kang YK, Zhan Z, Buters JT, Fojo T, et al. Paclitaxel-resistant human ovarian cancer cells have mutant beta-tubulins that exhibit impaired paclitaxel-driven polymerization. J Biol Chem. 1997;272:17118–25.

    Article  CAS  Google Scholar 

  67. Bhalla K, Huang Y, Tang C, Self S, Ray S, Mahoney ME, et al. Characterization of a human myeloid leukemia cell line highly resistant to taxol. Leukemia. 1994;8:465–75.

    CAS  Google Scholar 

  68. Ferlini C, Raspaglio G, Mozzetti S, Distefano M, Filippetti F, Martinelli E, et al. Bcl-2 down-regulation is a novel mechanism of paclitaxel resistance. Mol Pharm. 2003;64:51–8.

    Article  CAS  Google Scholar 

  69. Hari M, Loganzo F, Annable T, Tan X, Musto S, Morilla DB, et al. Paclitaxel-resistant cells have a mutation in the paclitaxel-binding region of beta-tubulin (Asp26Glu) and less stable microtubules. Mol Cancer Ther. 2006;5:270–8.

    Article  CAS  Google Scholar 

  70. Ferlini C, Raspaglio G, Mozzetti S, Cicchillitti L, Filippetti F, Gallo D, et al. The seco-taxane IDN5390 is able to target class III beta-tubulin and to overcome paclitaxel resistance. Cancer Res. 2005;65:2397–405.

    Article  CAS  Google Scholar 

  71. Ferlini C, Cicchillitti L, Raspaglio G, Bartollino S, Cimitan S, Bertucci C, et al. Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77. Cancer Res. 2009;69:6906–14.

    Article  CAS  Google Scholar 

  72. Wang L, Zhang F, Cui JY, Chen L, Chen YT, Liu BW. CAFs enhance paclitaxel resistance by inducing EMT through the IL6/JAK2/STAT3 pathway. Oncol Rep. 2018;39:2081–90.

    CAS  Google Scholar 

  73. Dean M. ABC transporters, drug resistance, and cancer stem cells. J Mammary Gland Biol Neoplasia. 2009;14:3–9.

    Article  Google Scholar 

  74. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5:275–84.

    Article  CAS  Google Scholar 

  75. Niu M, He Y, Xu J, Ding L, He T, Yi Y, et al. Noncanonical TGF-beta signaling leads to FBXO3-mediated degradation of DeltaNp63alpha promoting breast cancer metastasis and poor clinical prognosis. PLoS Biol. 2021;19:e3001113.

    Article  CAS  Google Scholar 

  76. Charan J, Kantharia ND. How to calculate sample size in animal studies? J Pharm Pharmacother. 2013;4:303–6.

    Article  Google Scholar 

  77. Yeh HW, Karmach O, Ji A, Carter D, Martins-Green MM, Ai HW. Red-shifted luciferase-luciferin pairs for enhanced bioluminescence imaging. Nat Methods. 2017;14:971–4.

    Article  CAS  Google Scholar 

  78. Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138:645–59.

    Article  CAS  Google Scholar 

  79. Li, F, Q Hu, T He, J Xu, Y Yi, S Xie, et al. The deubiquitinase USP4 stabilizes Twist1 protein to promote lung cancer cell stemness. Cancers (Basel). 2020;12:1582.

  80. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.

    Article  Google Scholar 

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Acknowledgements

We thank members of Z-XX laboratory for stimulating discussions during the study.

Funding

This work was supported by National Natural Science Foundation of China (81830108, 81861148031, and 31701242) to Z-XX or MN; National Key R&D Program of China (2018YFC2000100) to Z-XX; Department of Science and technology of Sichuan Province (23NSFSC3804) to MN; and the Fundamental Research Funds for the Central Universities (2021SCU12099) to MN.

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Z-XX and MN conceived the project and performed the project planning; FL, KQ, RG, YY, JX, LL, SX, MF, NW, WL, and MN performed research; FL, MN, and Z-XX contributed to data analyses; Z-XX, MN, and FL analyzed data and wrote the manuscript.

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Correspondence to Mengmeng Niu or Zhi-Xiong Jim Xiao.

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Li, F., Niu, M., Qin, K. et al. FBXL2 promotes E47 protein instability to inhibit breast cancer stemness and paclitaxel resistance. Oncogene 42, 339–350 (2023). https://doi.org/10.1038/s41388-022-02559-5

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