Skip to main content
SpringerLink
Log in

Targeting of JAK-STAT Signaling in Breast Cancer: Therapeutic Strategies to Overcome Drug Resistance

  • Chapter
  • First Online:
Breast Cancer Metastasis and Drug Resistance

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1152))

Abstract

Rapidly emerging ground-breaking discoveries have provided near to complete resolution of breast cancer signaling landscape and scientists have mapped the knowledge gaps associated with proteins encoded by the human genome. Based on the insights gleaned from decades of research, it seems clear that ligands transmit distinct information through specific receptors that is processed into characteristically unique biological outputs. Advances in imaging, structural biology, proteomics and genome editing have helped us to gain new insights into JAK-STAT signaling and how alterations in this pathway contributed to development of breast cancer and metastatic spread. Data obtained through high-throughput technologies has started to shed light on signal–transducer complexes formed during JAK-STAT signaling. Pharmacologists and molecular biologists are focusing on the strategies to therapeutically target this pathway to overcome drug resistance associated with breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Kaushik N, Kim MJ, Kim RK, Kumar Kaushik N, Seong KM, Nam SY, Lee SJ (2017) Low-dose radiation decreases tumor progression via the inhibition of the JAK1/STAT3 signaling axis in breast cancer cell lines. Sci Rep 7:43361. https://doi.org/10.1038/srep43361

    Article  PubMed  PubMed Central  Google Scholar 

  2. Kim SY, Kang JW, Song X, Kim BK, Yoo YD, Kwon YT, Lee YJ (2013) Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells. Cell Signal 25(4):961–969. https://doi.org/10.1016/j.cellsig.2013.01.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lee HJ, Seo NJ, Jeong SJ, Park Y, Jung DB, Koh W, Lee HJ, Lee EO, Ahn KS, Ahn KS, Lü J, Kim SH (2011) Oral administration of penta-O-galloyl-β-D-glucose suppresses triple-negative breast cancer xenograft growth and metastasis in strong association with JAK1-STAT3 inhibition. Carcinogenesis 32(6):804–811. https://doi.org/10.1093/carcin/bgr015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ahmad R, Raina D, Meyer C, Kufe D (2008) Triterpenoid CDDO-methyl ester inhibits the Janus-activated kinase-1 (JAK1)-->signal transducer and activator of transcription-3 (STAT3) pathway by direct inhibition of JAK1 and STAT3. Cancer Res 68(8):2920–2926. https://doi.org/10.1158/0008-5472.CAN-07-3036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rodriguez-Barrueco R, Yu J, Saucedo-Cuevas LP, Olivan M, Llobet-Navas D, Putcha P, Castro V, Murga-Penas EM, Collazo-Lorduy A, Castillo-Martin M, Alvarez M, Cordon-Cardo C, Kalinsky K, Maurer M, Califano A, Silva JM (2015) Inhibition of the autocrine IL-6-JAK2-STAT3-calprotectin axis as targeted therapy for HR-/HER2+ breast cancers. Genes Dev 29(15):1631–1648. https://doi.org/10.1101/gad.262642.115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nipin SP, Darvin P, Yoo YB, Joung YH, Kang DY, Kim DN, Hwang TS, Kim SY, Kim WS, Lee HK, Cho BW, Kim HS, Park KD, Park JH, Chang SH, Yang YM (2015) The combination of methylsulfonylmethane and tamoxifen inhibits the Jak2/STAT5b pathway and synergistically inhibits tumor growth and metastasis in ER-positive breast cancer xenografts. BMC Cancer 15:474. https://doi.org/10.1186/s12885-015-1445-0

    Article  CAS  Google Scholar 

  7. Liu X, Xiao Q, Bai X, Yu Z, Sun M, Zhao H, Mi X, Wang E, Yao W, Jin F, Zhao L, Ren J, Wei M (2014) Activation of STAT3 is involved in malignancy mediated by CXCL12-CXCR4 signaling in human breast cancer. Oncol Rep 32(6):2760–2768. https://doi.org/10.3892/or.2014.3536. Epub 2014 Oct 10

    Article  CAS  PubMed  Google Scholar 

  8. Wang X, Qiu W, Zhang G, Xu S, Gao Q, Yang Z (2015) MicroRNA-204 targets JAK2 in breast cancer and induces cell apoptosis through the STAT3/BCl-2/survivin pathway. Int J Clin Exp Pathol 8(5):5017–5025. eCollection 2015

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Ma S, Liu M, Xu Z, Li Y, Guo H, Ge Y, Liu Y, Zheng D, Shi J (2016) A double feedback loop mediated by microRNA-23a/27a/24-2 regulates M1 versus M2 macrophage polarization and thus regulates cancer progression. Oncotarget 7(12):13502–13519. https://doi.org/10.18632/oncotarget.6284

    Article  PubMed  Google Scholar 

  10. Ahn R, Sabourin V, Bolt AM, Hébert S, Totten S, De Jay N, Festa MC, Young YK, Im YK, Pawson T, Koromilas AE, Muller WJ, Mann KK, Kleinman CL, Ursini-Siegel J (2017) The Shc1 adaptor simultaneously balances Stat1 and Stat3 activity to promote breast cancer immune suppression. Nat Commun 8:14638. https://doi.org/10.1038/ncomms14638

    Article  PubMed  PubMed Central  Google Scholar 

  11. Browne AL, Charmsaz S, Varešlija D, Fagan A, Cosgrove N, Cocchiglia S, Purcell S, Ward E, Bane F, Hudson L, Hill AD, Carroll JS, Redmond AM, Young LS (2018) Network analysis of SRC-1 reveals a novel transcription factor hub which regulates endocrine resistant breast cancer. Oncogene. https://doi.org/10.1038/s41388-017-0042-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lu P, Gu Y, Li L, Wang F, Yang X, Yang Y (2017) Long noncoding RNA CAMTA1 promotes proliferation and mobility of human breast cancer cell line MDA- MB-231 via targeting miR-20b. Oncol Res. https://doi.org/10.3727/096504017X14953948675395

    Article  Google Scholar 

  13. Jeon M, You D, Bae SY, Kim SW, Nam SJ, Kim HH, Kim S, Lee JE (2016) Dimerization of EGFR and HER2 induces breast cancer cell motility through STAT1-dependent ACTA2 induction. Oncotarget 8(31):50570–50581. https://doi.org/10.18632/oncotarget.10843

    Article  PubMed  PubMed Central  Google Scholar 

  14. Darvin P, Joung YH, Kang DY, Sp N, Byun HJ, Hwang TS, Sasidharakurup H, Lee CH, Cho KH, Park KD, Lee HK, Yang YM (2017) Tannic acid inhibits EGFR/STAT1/3 and enhances p38/STAT1 signalling axis in breast cancer cells. J Cell Mol Med 21(4):720–734. https://doi.org/10.1111/jcmm.13015

    Article  CAS  PubMed  Google Scholar 

  15. Ogony J, Choi HJ, Lui A, Cristofanilli M, Lewis-Wambi J (2016) Interferon-induced transmembrane protein 1 (IFITM1) overexpression enhances the aggressive phenotype of SUM149 inflammatory breast cancer cells in a signal transducer and activator of transcription 2 (STAT2)-dependent manner. Breast Cancer Res 18(1):25. https://doi.org/10.1186/s13058-016-0683-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yates LR, Knappskog S, Wedge D, Farmery JHR, Gonzalez S, Martincorena I, Alexandrov LB, Van Loo P, Haugland HK, Lilleng PK, Gundem G, Gerstung M, Pappaemmanuil E, Gazinska P, Bhosle SG, Jones D, Raine K, Mudie L, Latimer C, Sawyer E, Desmedt C, Sotiriou C, Stratton MR, Sieuwerts AM, Lynch AG, Martens JW, Richardson AL, Tutt A, Lønning PE, Campbell PJ (2017) Genomic evolution of breast cancer metastasis and relapse. Cancer Cell 32(2):169–184.e7. https://doi.org/10.1016/j.ccell.2017.07.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang W, Guo J, Li S, Ma T, Xu D, Han C, Liu F, Yu W, Kong L (2017) Discovery of monocarbonyl curcumin-BTP hybrids as STAT3 inhibitors for drug-sensitive and drug-resistant breast cancer therapy. Sci Rep 7:46352. https://doi.org/10.1038/srep46352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li X, Ma H, Li L, Chen Y, Sun X, Dong Z, Liu JY, Zhu W, Zhang JT (2018b) Novel synthetic bisindolylmaleimide alkaloids inhibit STAT3 activation by binding to the SH2 domain and suppress breast xenograft tumor growth. Oncogene. https://doi.org/10.1038/s41388-017-0076-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Noman MAA, Hossain T, Ahsan M, Jamshidi S, Hasan CM, Rahman KM (2018) Crispenes F and G, cis-clerodane furanoditerpenoids from tinospora crispa, inhibit STAT3 dimerization. J Nat Prod 81(2):236–242. https://doi.org/10.1021/acs.jnatprod.7b00377

    Article  CAS  PubMed  Google Scholar 

  20. Cui L, Bu W, Song J, Feng L, Xu T, Liu D, Ding W, Wang J, Li C, Ma B, Luo Y, Jiang Z, Wang C, Chen J, Hou J, Yan H, Yang L, Jia X (2017) Apoptosis induction by alantolactone in breast cancer MDA-MB-231 cells through reactive oxygen species-mediated mitochondrion-dependent pathway. Arch Pharm Res. https://doi.org/10.1007/s12272-017-0990-2

    Article  PubMed  Google Scholar 

  21. Wang J, Xu J, Xing G (2017) Lycorine inhibits the growth and metastasis of breast cancer through the blockage of STAT3 signaling pathway. Acta Biochim Biophys Sin Shanghai 49(9):771–779. https://doi.org/10.1093/abbs/gmx076

    Article  CAS  PubMed  Google Scholar 

  22. Liu CY, Huang TT, Chu PY, Huang CT, Lee CH, Wang WL, Lau KY, Tsai WC, Chao TI, Su JC, Chen MH, Shiau CW, Tseng LM, Chen KF (2017) The tyrosine kinase inhibitor nintedanib activates SHP-1 and induces apoptosis in triple-negative breast cancer cells. Exp Mol Med 49(8):e366. https://doi.org/10.1038/emm.2017.114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chuang YF, Huang SW, Hsu YF, Yu MC, Ou G, Huang WJ, Hsu MJ (2017) WMJ-8-B, a novel hydroxamate derivative, induces MDA-MB-231 breast cancer cell death via the SHP-1-STAT3-survivin cascade. Br J Pharmacol 174(17):2941–2961. https://doi.org/10.1111/bph.13929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kim HS, Kim T, Ko H, Lee J, Kim YS, Suh YG (2017) Identification of galiellalactone-based novel STAT3-selective inhibitors with cytotoxic activities against triple-negative breast cancer cell lines. Bioorg Med Chem 25(19):5032–5040. https://doi.org/10.1016/j.bmc.2017.06.036

    Article  CAS  PubMed  Google Scholar 

  25. Sirkisoon SR, Carpenter RL, Rimkus T, Anderson A, Harrison A, Lange AM, Jin G, Watabe K, Lo HW (2018) Interaction between STAT3 and GLI1/tGLI1 oncogenic transcription factors promotes the aggressiveness of triple-negative breast cancers and HER2-enriched breast cancer. Oncogene. https://doi.org/10.1038/s41388-018-0132-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li L, Sun B, Gao Y, Niu H, Yuan H, Lou H (2018a) STAT3 contributes to lysosomal-mediated cell death in a novel derivative of riccardin D-treated breast cancer cells in association with TFEB. Biochem Pharmacol 150:267–279. https://doi.org/10.1016/j.bcp.2018.02.026. [Epub ahead of print]

    Article  CAS  PubMed  Google Scholar 

  27. Sasi W, Jiang WG, Sharma A, Mokbel K (2010) Higher expression levels of SOCS 1,3,4,7 are associated with earlier tumour stage and better clinical outcome in human breast cancer. BMC Cancer 10:178. https://doi.org/10.1186/1471-2407-10-178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gao Y, Cimica V, Reich NC (2012) Suppressor of cytokine signaling 3 inhibits breast tumor kinase activation of STAT3. J Biol Chem 287(25):20904–20912. https://doi.org/10.1074/jbc.M111.334144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kuo PL, Ni WC, Tsai EM, Hsu YL (2009) Dehydrocostuslactone disrupts signal transducers and activators of transcription 3 through up-regulation of suppressor of cytokine signaling in breast cancer cells. Mol Cancer Ther 8(5):1328–1339. https://doi.org/10.1158/1535-7163.MCT-08-0914

    Article  CAS  PubMed  Google Scholar 

  30. Wang Z, Han J, Cui Y, Zhou X, Fan K (2013) miRNA-21 inhibition enhances RANTES and IP-10 release in MCF-7 via PIAS3 and STAT3 signalling and causes increased lymphocyte migration. Biochem Biophys Res Commun 439(3):384–389. https://doi.org/10.1016/j.bbrc.2013.08.072

    Article  CAS  PubMed  Google Scholar 

  31. Liu S, Li L, Zhang Y, Zhang Y, Zhao Y, You X, Lin Z, Zhang X, Ye L (2012) The oncoprotein HBXIP uses two pathways to up-regulate S100A4 in promotion of growth and migration of breast cancer cells. J Biol Chem 287(36):30228–30239. https://doi.org/10.1074/jbc.M112.343947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nandy SB, Orozco A, Lopez-Valdez R, Roberts R, Subramani R, Arumugam A, Dwivedi AK, Stewart V, Prabhakar G, Jones S, Lakshmanaswamy R (2017) Glucose insult elicits hyperactivation of cancer stem cells through miR-424-cdc42-prdm14 signalling axis. Br J Cancer 117(11):1665–1675. https://doi.org/10.1038/bjc.2017.335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mapes J, Anandan L, Li Q, Neff A, Clevenger CV, Bagchi IC, Bagchi MK (2018) Aberrantly high expression of the CUB and zona pellucida-like domain-containing protein 1 (CUZD1) in mammary epithelium leads to breast tumorigenesis. J Biol Chem 293(8):2850–2864. https://doi.org/10.1074/jbc.RA117.000162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Bioinformatics and Biotechnology, International Islamic University, Islamabad, Pakistan

    Sobia Tabassum

  2. Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan

    Rashda Abbasi, Nafees Ahmad & Ammad Ahmad Farooqi

Authors
  1. Sobia Tabassum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rashda Abbasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nafees Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ammad Ahmad Farooqi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ammad Ahmad Farooqi .

Editor information

Editors and Affiliations

  1. Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA

    Aamir Ahmad

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Tabassum, S., Abbasi, R., Ahmad, N., Farooqi, A.A. (2019). Targeting of JAK-STAT Signaling in Breast Cancer: Therapeutic Strategies to Overcome Drug Resistance. In: Ahmad, A. (eds) Breast Cancer Metastasis and Drug Resistance. Advances in Experimental Medicine and Biology, vol 1152. Springer, Cham. https://doi.org/10.1007/978-3-030-20301-6_14

Download citation

Publish with us

Policies and ethics

Search

Navigation