Skip to main content
SpringerLink
Log in

Role of mTORC1 and mTORC2 in Breast Cancer: Therapeutic Targeting of mTOR and Its Partners to Overcome Metastasis and 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

Based on the insights gleaned from decades of research, it seems clear that mechanistic target of rapamycin (mTOR) is an essential signaling node that integrates environmental clues for regulation of cell survival, metabolism and proliferation of the cells. However, overwhelmingly increasing scientific evidence has added a new layer of intricacy to already complicated and versatile signaling pathway of mTOR. Deregulation of spatio-temporally controlled mTOR-driven pathway played contributory role in breast cancer development and progression. Pharmacologists and molecular biologists have specifically emphasized on the identification and development of mTOR-pathway inhibitors. In this chapter we have attempted to provide an overview of the most recent findings related to therapeutic targeting of mTOR-associated mTORC1 and mTORC2 in breast cancer. We have also comprehensively summarized regulation of mTOR and its partners by microRNAs in 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. Alayev A, Salamon RS, Berger SM, Schwartz NS, Cuesta R, Snyder RB, Holz MK (2016) mTORC1 directly phosphorylates and activates ERα upon estrogen stimulation. Oncogene 35(27):3535–3543. https://doi.org/10.1038/onc.2015.414

    Article  CAS  PubMed  Google Scholar 

  2. Balakrishnan S, Mukherjee S, Das S, Bhat FA, Raja Singh P, Patra CR, Arunakaran J (2017) Gold nanoparticles-conjugated quercetin induces apoptosis via inhibition of EGFR/PI3K/Akt-mediated pathway in breast cancer cell lines (MCF-7 and MDA-MB-231). Cell Biochem Funct 35(4):217–231. https://doi.org/10.1002/cbf.3266

    Article  CAS  PubMed  Google Scholar 

  3. Blanco E, Sangai T, Wu S, Hsiao A, Ruiz-Esparza GU, Gonzalez-Delgado CA et al (2014) Colocalized delivery of rapamycin and paclitaxel to tumors enhances synergistic targeting of the PI3K/Akt/mTOR pathway. Mol Ther 22(7):1310–1319

    Article  CAS  Google Scholar 

  4. Chen J, Zhu Y, Zhang W, Peng X, Zhou J, Li F, Han B, Liu X, Ou Y, Yu X (2018) Delphinidin induced protective autophagy via mTOR pathway suppression and AMPK pathway activation in HER-2 positive breast cancer cells. BMC Cancer 18(1):342. https://doi.org/10.1186/s12885-018-4231-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Guru SK, Pathania AS, Kumar S, Ramesh D, Kumar M, Rana S, Kumar A, Malik F, Sharma PR, Chandan BK, Jaglan S, Sharma JP, Shah BA, Tasduq SA, Lattoo SK, Faruk A, Saxena AK, Vishwakarma RA, Bhushan S (2015) Secalonic acid-D represses HIF1α/VEGF-mediated angiogenesis by regulating the Akt/mTOR/p70S6K signaling cascade. Cancer Res 75(14):2886–2896. https://doi.org/10.1158/0008-5472.CAN-14-2312

    Article  CAS  PubMed  Google Scholar 

  6. Jung CH, Kim H, Ahn J, Jung SK, Um MY, Son KH, Kim TW, Ha TY (2013) Anthricin isolated from Anthriscus sylvestris (L.) Hoffm. Inhibits the growth of breast cancer cells by inhibiting Akt/mTOR signaling, and its apoptotic effects are enhanced by autophagy inhibition. Evid Based Complement Alternat Med 2013:385219. https://doi.org/10.1155/2013/385219

    Article  PubMed  PubMed Central  Google Scholar 

  7. Ke K, Lou T (2017) MicroRNA-10a suppresses breast cancer progression via PI3K/Akt/mTOR pathway. Oncol Lett 14(5):5994–6000. https://doi.org/10.3892/ol.2017.6930.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Li W, Wang H, Zhang J, Zhai L, Chen W, Zhao C (2016a) miR-199a-5p regulates β1 integrin through Ets-1 to suppress invasion in breast cancer. Cancer Sci 107(7):916–923. https://doi.org/10.1111/cas.12952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li W, Zhai L, Wang H, Liu C, Zhang J, Chen W, Wei Q (2016b) Downregulation of LncRNA GAS5 causes trastuzumab resistance in breast cancer. Oncotarget 7(19):27778–27786. https://doi.org/10.18632/oncotarget.8413

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lineham E, Tizzard GJ, Coles SJ, Spencer J, Morley SJ (2018) Synergistic effects of inhibiting the MNK-eIF4E and PI3K/AKT/ mTOR pathways on cell migration in MDA-MB-231 cells. Oncotarget 9(18):14148–14159. https://doi.org/10.18632/oncotarget.24354

    Article  PubMed  PubMed Central  Google Scholar 

  11. Lu W, Lin C, Li Y (2014) Rottlerin induces Wnt co-receptor LRP6 degradation and suppresses both Wnt/β-catenin and mTORC1 signaling in prostate and breast cancer cells. Cell Signal 26(6):1303–1309. https://doi.org/10.1016/j.cellsig.2014.02.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Makhov P, Golovine K, Teper E, Kutikov A, Mehrazin R, Corcoran A, Tulin A, Uzzo RG, Kolenko VM (2014) Piperlongumine promotes autophagy via inhibition of Akt/mTOR signalling and mediates cancer cell death. Br J Cancer 110(4):899–907. https://doi.org/10.1038/bjc.2013.810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Martin EC, Rhodes LV, Elliott S, Krebs AE, Nephew KP, Flemington EK, Collins-Burow BM, Burow ME (2014) microRNA regulation of mammalian target of rapamycin expression and activity controls estrogen receptor function and RAD001 sensitivity. Mol Cancer 13:229. https://doi.org/10.1186/1476-4598-13-229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mateo F, Arenas EJ, Aguilar H, Serra-Musach J, de Garibay GR, Boni J, Maicas M, Du S, Iorio F, Herranz-Ors C, Islam A, Prado X, Llorente A, Petit A, Vidal A, Català I, Soler T, Venturas G, Rojo-Sebastian A, Serra H, Cuadras D, Blanco I, Lozano J, Canals F, Sieuwerts AM, de Weerd V, Look MP, Puertas S, García N, Perkins AS, Bonifaci N, Skowron M, Gómez-Baldó L et al (2017) Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition. Oncogene 36(19):2737–2749. https://doi.org/10.1038/onc.2016.427

    Article  CAS  PubMed  Google Scholar 

  15. Mi W, Ye Q, Liu S, She QB (2015) AKT inhibition overcomes rapamycin resistance by enhancing the repressive function of PRAS40 on mTORC1/4E-BP1 axis. Oncotarget 6(16):13962–13977

    Article  Google Scholar 

  16. Michaloglou C, Crafter C, Siersbæk R, Delpuech O, Curwen JO, Carnevalli LS, Staniszewska AD, Polanska UM, Cheraghchi-Bashi A, Lawson M, Chernukhin I, McEwen R, Carroll JS, Cosulich SC (2018. pii: molcanther.0537.2017) Combined inhibition of mTOR and CDK4/6 is required for optimal blockade of E2F function and long term growth inhibition in estrogen receptor positive breast cancer. Mol Cancer Ther. https://doi.org/10.1158/1535-7163.MCT-17-0537

    Article  CAS  Google Scholar 

  17. Morrison Joly M, Hicks DJ, Jones B, Sanchez V, Estrada MV, Young C, Williams M, Rexer BN, Sarbassov dos D, Muller WJ, Brantley-Sieders D, Cook RS (2016) Rictor/mTORC2 drives progression and therapeutic resistance of HER2-amplified breast cancers. Cancer Res 76(16):4752–4764. https://doi.org/10.1158/0008-5472.CAN-15-3393

    Article  CAS  PubMed  Google Scholar 

  18. Morrison Joly M, Williams MM, Hicks DJ, Jones B, Sanchez V, Young CD, Sarbassov DD, Muller WJ, Brantley-Sieders D, Cook RS (2017) Two distinct mTORC2-dependent pathways converge on Rac1 to drive breast cancer metastasis. Breast Cancer Res 19(1):74. https://doi.org/10.1186/s13058-017-0868-8.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Parhi P, Sahoo SK (2015) Trastuzumab guided nanotheranostics: a lipid based multifunctional nanoformulation for targeted drug delivery and imaging in breast cancer therapy. J Colloid Interface Sci 451:198–211

    Article  CAS  Google Scholar 

  20. Phua YW, Nguyen A, Roden DL, Elsworth B, Deng N, Nikolic I, Yang J, Mcfarland A, Russell R, Kaplan W, Cowley MJ, Nair R, Zotenko E, O’Toole S, Tan SX, James DE, Clark SJ, Kouros-Mehr H, Swarbrick A (2015) MicroRNA profiling of the pubertal mouse mammary gland identifies miR-184 as a candidate breast tumour suppressor gene. Breast Cancer Res 17:83. https://doi.org/10.1186/s13058-015-0593-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Polchi A, Magini A, Mazuryk J, Tancini B, Gapinski J, Patkowski A et al (2016) Rapamycin loaded solid lipid nanoparticles as a new tool to deliver mTOR inhibitors: formulation and in vitro characterization. Nanomaterials (Basel) 6(5):87

    Article  Google Scholar 

  22. Wang Y, Han E, Xing Q, Yan J, Arrington A, Wang C, Tully D, Kowolik CM, Lu DM, Frankel PH, Zhai J, Wen W, Horne D, Yip MLR, Yim JH (2015) Baicalein upregulates DDIT4 expression which mediates mTOR inhibition and growth inhibition in cancer cells. Cancer Lett 358(2):170–179. https://doi.org/10.1016/j.canlet.2014.12.033

    Article  CAS  PubMed  Google Scholar 

  23. Wang J, Wang Y, Liu Q, Yang L, Zhu R, Yu C, Wang S (2016) Rational design of multifunctional dendritic mesoporous silica nanoparticles to load curcumin and enhance efficacy for breast cancer therapy. ACS Appl Mater Interfaces 8(40):26511–26523

    Article  CAS  Google Scholar 

  24. Zhang Y, Xu S, Lin J, Yao G, Han Z, Liang B, Zou Z, Chen Z, Song Q, Dai Y, Gao T, Liu A, Bai X (2012) mTORC1 is a target of nordihydroguaiaretic acid to prevent breast tumor growth in vitro and in vivo. Breast Cancer Res Treat 136(2):379–388. https://doi.org/10.1007/s10549-012-2270-7

    Article  CAS  PubMed  Google Scholar 

  25. Zhang Y, Zhang HE, Liu Z (2016) MicroRNA-147 suppresses proliferation, invasion and migration through the AKT/mTOR signaling pathway in breast cancer. Oncol Lett 11(1):405–410

    Article  CAS  Google Scholar 

  26. Zhou X, Yue GG, Chan AM, Tsui SK, Fung KP, Sun H, Pu J, Lau CB (2017a) Eriocalyxin B, a novel autophagy inducer, exerts anti-tumor activity through the suppression of Akt/mTOR/p70S6K signaling pathway in breast cancer. Biochem Pharmacol 142:58–70. https://doi.org/10.1016/j.bcp.2017.06.133

    Article  CAS  PubMed  Google Scholar 

  27. Zhou R, Chen H, Chen J, Chen X, Wen Y, Xu L (2018) Extract from Astragalus membranaceus inhibit breast cancer cells proliferation via PI3K/AKT/mTOR signaling pathway. BMC Complement Altern Med 18(1):83. https://doi.org/10.1186/s12906-018-2148-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Botany, GCU, Lahore, Pakistan

    Ghazala Butt

  2. Lahore College for Women University, Lahore, Pakistan

    Durray Shahwar

  3. Department of Chemistry, GCU, Lahore, Pakistan

    Muhammad Zahid Qureshi

  4. Department of Obstetrics and Gynecology, Faculty of Medicine, Yeditepe University, Istanbul, Turkey

    Rukset Attar

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

    Misbah Akram

  6. Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey

    Yelda Birinci

  7. Department of Pharmacognosy, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey

    Gokce Seker Karatoprak

  8. Department of Gynecology and Obstetrics, University Hospital of Bern and University of Bern, Bern, Switzerland

    Maria Luisa Gasparri

  9. Department of Gynecology and Obstetrics, “Sapienza” University of Rome, Rome, Italy

    Maria Luisa Gasparri

  10. Surgical and Medical Department of Translational Medicine, “Sapienza” University of Rome, Rome, Italy

    Maria Luisa Gasparri

  11. Laboratory for Translational Oncology and Personalized Medicine, RLMC, Lahore, Pakistan

    Ammad Ahmad Farooqi

Authors
  1. Ghazala Butt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Durray Shahwar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Muhammad Zahid Qureshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rukset Attar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Misbah Akram
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yelda Birinci
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gokce Seker Karatoprak
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Maria Luisa Gasparri
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ammad Ahmad Farooqi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ghazala Butt .

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

Butt, G. et al. (2019). Role of mTORC1 and mTORC2 in Breast Cancer: Therapeutic Targeting of mTOR and Its Partners to Overcome Metastasis and 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_15

Download citation

Publish with us

Policies and ethics

Search

Navigation