Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The miR-186-3p/EREG axis orchestrates tamoxifen resistance and aerobic glycolysis in breast cancer cells

Oncogene volume 38, pages 5551–5565 (2019)Cite this article

Subjects

Abstract

Tamoxifen resistance is one of the major challenges for its medical uses in estrogen receptor (ER)-positive breast cancer. Aerobic glycolysis, an anomalous characteristic of glucose metabolism in cancer cells, has been shown to associate with the resistance to chemotherapeutic agents. It remains, however, largely unclear whether and how tamoxifen resistance contributes to aerobic glycolysis in breast cancer. Here, we report that tamoxifen resistance is associated with enhanced glycolysis in ER-positive breast cancer cells. We demonstrate that EREG, an agonist of EGFR, has an important role in enhancing glycolysis via activating EGFR signaling and its downstream glycolytic genes in tamoxifen-resistant breast cancer cells. We further show that EREG is a direct target of miR-186-3p and that downregulation of miR-186-3p by tamoxifen results in EREG upregulation in tamoxifen-resistant breast cancer cells. Importantly, systemic delivery of cholesterol-modified agomiR-186-3p to mice bearing tamoxifen-resistant breast tumors effectively attenuates both tumor growth and [18F]-fluoro-deoxyglucose ([18F]-FDG) uptake. Together, our results reveal a novel molecular mechanism of resistance to hormone therapies in which the miR-186-3p/EREG axis orchestrates tamoxifen resistance and aerobic glycolysis in ER-positive breast cancer, suggesting targeting miR-186-3p as a promising strategy for therapeutic intervention in endocrine-resistant breast tumors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Jaiyesimi IA, Buzdar AU, Decker DA, Hortobagyi GN. Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol. 1995;13:513–29.

    Article  CAS  Google Scholar 

  2. Mills JN, Rutkovsky AC, Giordano A. Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors. Curr Opin Pharm. 2018;41:59–65.

    Article  CAS  Google Scholar 

  3. Ma CX, Sanchez CG, Ellis MJ. Predicting endocrine therapy responsiveness in breast cancer. Oncol (Williston Park). 2009;23:133–42.

    Google Scholar 

  4. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687–717.

  5. Toy W, Shen Y, Won H, Green B, Sakr RA, Will M, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45:1439–45.

    Article  CAS  Google Scholar 

  6. Torres-Arzayus MI, Font de Mora J, Yuan J, Vazquez F, Bronson R, Rue M, et al. High tumor incidence and activation of the PI3K/AKT pathway in transgenic mice define AIB1 as an oncogene. Cancer Cell. 2004;6:263–74.

    Article  CAS  Google Scholar 

  7. Johnston SR. Enhancing endocrine therapy for hormone receptor-positive advanced breast cancer: cotargeting signaling pathways. J Natl Cancer Inst. 2015;107:djv212.

    Article  Google Scholar 

  8. Santen RJ, Fan P, Zhang Z, Bao Y, Song RX, Yue W. Estrogen signals via an extra-nuclear pathway involving IGF-1R and EGFR in tamoxifen-sensitive and -resistant breast cancer cells. Steroids. 2009;74:586–94.

    Article  CAS  Google Scholar 

  9. Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer’s Achilles’ heel. Cancer Cell. 2008;13:472–82.

    Article  CAS  Google Scholar 

  10. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.

    Article  Google Scholar 

  11. Swietach P, Vaughan-Jones RD, Harris AL. Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastas Rev. 2007;26:299–310.

    Article  CAS  Google Scholar 

  12. Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 2007;109:3812–9.

    Article  CAS  Google Scholar 

  13. Bhattacharya B, Mohd Omar MF, Soong R. The Warburg effect and drug resistance. Br J Pharm. 2016;173:970–9.

    Article  CAS  Google Scholar 

  14. Morandi A, Indraccolo S. Linking metabolic reprogramming to therapy resistance in cancer. Biochim Biophys Acta. 2017;1868:1–6.

    CAS  Google Scholar 

  15. Knowlden JM, Hutcheson IR, Jones HE, Madden T, Gee JM, Harper ME, et al. Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology. 2003;144:1032–44.

    Article  CAS  Google Scholar 

  16. Shelly M, Pinkas-Kramarski R, Guarino BC, Waterman H, Wang LM, Lyass L, et al. Epiregulin is a potent pan-ErbB ligand that preferentially activates heterodimeric receptor complexes. J Biol Chem. 1998;273:10496–505.

    Article  CAS  Google Scholar 

  17. Sunaga N, Kaira K, Imai H, Shimizu K, Nakano T, Shames DS, et al. Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer. Oncogene. 2013;32:4034–42.

    Article  CAS  Google Scholar 

  18. Qu X, Sandmann T, Frierson H Jr., Fu L, Fuentes E, et al. Integrated genomic analysis of colorectal cancer progression reveals activation of EGFR through demethylation of the EREG promoter. Oncogene. 2016;35:6403–15.

    Article  CAS  Google Scholar 

  19. Zhu Z, Kleeff J, Friess H, Wang L, Zimmermann A, Yarden Y, et al. Epiregulin is up-regulated in pancreatic cancer and stimulates pancreatic cancer cell growth. Biochem Biophys Res Commun. 2000;273:1019–24.

    Article  CAS  Google Scholar 

  20. Torring N, Jorgensen PE, Sorensen BS, Nexo E. Increased expression of heparin binding EGF (HB-EGF), amphiregulin, TGF alpha and epiregulin in androgen-independent prostate cancer cell lines. Anticancer Res. 2000;20:91–95.

    CAS  PubMed  Google Scholar 

  21. Revillion F, Lhotellier V, Hornez L, Bonneterre J, Peyrat JP. ErbB/HER ligands in human breast cancer, and relationships with their receptors, the bio-pathological features and prognosis. Ann Oncol. 2008;19:73–80.

    Article  CAS  Google Scholar 

  22. Zhao S, Liu MF. Mechanisms of microRNA-mediated gene regulation. Sci China C Life Sci. 2009;52:1111–6.

    Article  CAS  Google Scholar 

  23. Mishra S, Yadav T, Rani V. Exploring miRNA based approaches in cancer diagnostics and therapeutics. Crit Rev Oncol Hematol. 2016;98:12–23.

    Article  Google Scholar 

  24. Zhang LF, Jiang S, Liu MF. MicroRNA regulation and analytical methods in cancer cell metabolism. Cell Mol Life Sci. 2017;74:2929–41.

    Article  CAS  Google Scholar 

  25. Ma J, Dong C, Ji C. MicroRNA and drug resistance. Cancer Gene Ther. 2010;17:523–31.

    Article  CAS  Google Scholar 

  26. Thrane S, Pedersen AM, Thomsen MB, Kirkegaard T, Rasmussen BB, Duun-Henriksen AK, et al. A kinase inhibitor screen identifies Mcl-1 and Aurora kinase A as novel treatment targets in antiestrogen-resistant breast cancer cells. Oncogene. 2015;34:4199–210.

    Article  CAS  Google Scholar 

  27. Schneider MR, Wolf E. The epidermal growth factor receptor ligands at a glance. J Cell Physiol. 2009;218:460–6.

    Article  CAS  Google Scholar 

  28. Lim SO, Li CW, Xia W, Lee HH, Chang SS, Shen J, et al. EGFR signaling enhances aerobic glycolysis in triple-negative breast cancer cells to promote tumor growth and immune escape. Cancer Res. 2016;76:1284–96.

    Article  CAS  Google Scholar 

  29. Poliakova M, Aebersold DM, Zimmer Y, Medova M. The relevance of tyrosine kinase inhibitors for global metabolic pathways in cancer. Mol Cancer. 2018;17:27.

    Article  Google Scholar 

  30. Lin S, Gregory RI. MicroRNA biogenesis pathways in cancer. Nat Rev Cancer. 2015;15:321–33.

    Article  CAS  Google Scholar 

  31. Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120:15–20.

    Article  CAS  Google Scholar 

  32. Connor CE, Norris JD, Broadwater G, Willson TM, Gottardis MM, Dewhirst MW, et al. Circumventing tamoxifen resistance in breast cancers using antiestrogens that induce unique conformational changes in the estrogen receptor. Cancer Res. 2001;61:2917–22.

    CAS  PubMed  Google Scholar 

  33. Gee JM, Harper ME, Hutcheson IR, Madden TA, Barrow D, Knowlden JM, et al. The antiepidermal growth factor receptor agent gefitinib (ZD1839/Iressa) improves antihormone response and prevents development of resistance in breast cancer in vitro. Endocrinology. 2003;144:5105–17.

    Article  CAS  Google Scholar 

  34. Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S, et al. Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res. 2008;68:826–33.

    Article  CAS  Google Scholar 

  35. Peifer C, Alessi DR. New anti-cancer role for PDK1 inhibitors: preventing resistance to tamoxifen. Biochem J. 2009;417:e5–7.

    Article  CAS  Google Scholar 

  36. Iorns E, Lord CJ, Ashworth A. Parallel RNAi and compound screens identify the PDK1 pathway as a target for tamoxifen sensitization. Biochem J. 2009;417:361–70.

    Article  CAS  Google Scholar 

  37. Daurio NA, Tuttle SW, Worth AJ, Song EY, Davis JM, Snyder NW, et al. AMPK activation and metabolic reprogramming by tamoxifen through estrogen receptor-independent mechanisms suggests new uses for this therapeutic modality in cancer treatment. Cancer Res. 2016;76:3295–306.

    Article  CAS  Google Scholar 

  38. Zhu X, Shen H, Yin X, Long L, Xie C, Liu Y, et al. miR-186 regulation of Twist1 and ovarian cancer sensitivity to cisplatin. Oncogene. 2016;35:323–32.

    Article  CAS  Google Scholar 

  39. Ye J, Zhang Z, Sun L, Fang Y, Xu X, Zhou G. miR-186 regulates chemo-sensitivity to paclitaxel via targeting MAPT in non-small cell lung cancer (NSCLC). Mol Biosyst. 2016;12:3417–24.

    Article  CAS  Google Scholar 

  40. Li C, Gao Y, Li Y, Ding D. TUG1 mediates methotrexate resistance in colorectal cancer via miR-186/CPEB2 axis. Biochem Biophys Res Commun. 2017;491:552–7.

    Article  CAS  Google Scholar 

  41. Sun P, Hu JW, Xiong WJ, Mi J. miR-186 regulates glycolysis through Glut1 during the formation of cancer-associated fibroblasts. Asian Pac J Cancer Prev. 2014;15:4245–50.

    Article  Google Scholar 

  42. Liu L, Wang Y, Bai R, Yang K, Tian Z. MiR-186 inhibited aerobic glycolysis in gastric cancer via HIF-1alpha regulation. Oncogenesis. 2016;5:e224.

    Article  CAS  Google Scholar 

  43. Park WC, Liu H, Macgregor Schafer J, Jordan VC. Deregulation of estrogen induced telomerase activity in tamoxifen-resistant breast cancer cells. Int J Oncol. 2005;27:1459–66.

    CAS  PubMed  Google Scholar 

  44. ANSI/ATCC ASN-0002-2011. Authentication of human cell lines: standardization of STR profiling. http://webstore.ansi.org/RecordDetail.aspx?sku=ANSI%2fATCC+ASN-0002-2011.

  45. Wang L, Zhang LF, Wu J, Xu SJ, Xu YY, Li D, et al. IL-1beta-mediated repression of microRNA-101 is crucial for inflammation-promoted lung tumorigenesis. Cancer Res. 2014;74:4720–30.

    Article  CAS  Google Scholar 

  46. Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley DR, et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc. 2012;7:562–78.

    Article  CAS  Google Scholar 

  47. Zhang LF, Lou JT, Lu MH, Gao C, Zhao S, Li B, et al. Suppression of miR-199a maturation by HuR is crucial for hypoxia-induced glycolytic switch in hepatocellular carcinoma. Embo J. 2015;34:2671–85.

    Article  CAS  Google Scholar 

  48. Jiang S, Zhang LF, Zhang HW, Hu S, Lu MH, Liang S, et al. A novel miR-155/miR-143 cascade controls glycolysis by regulating hexokinase 2 in breast cancer cells. Embo J. 2012;31:1985–98.

    Article  CAS  Google Scholar 

  49. Miao Y, Zhang LF, Guo R, Liang S, Zhang M, Shi S, et al. (18)F-FDG PET/CT for monitoring the response of breast cancer to miR-143-based therapeutics by targeting tumor glycolysis. Mol Ther Nucleic Acids. 2016;5:e357.

    Article  CAS  Google Scholar 

  50. Gambhir SS, Bauer E, Black ME, Liang Q, Kokoris MS, Barrio JR, et al. A mutant herpes simplex virus type 1 thymidine kinase reporter gene shows improved sensitivity for imaging reporter gene expression with positron emission tomography. Proc Natl Acad Sci USA. 2000;97:2785–90.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank members of the Chen’s and Zhu’s labs for helpful comments. This work was supported by grants from the National Natural Science Foundation of China (81272544 and 81502267) and Foundation and frontier science and technology project of Yuzhong district science and technology commission, Chongqing, China (20150121).

Author information

Author notes

  1. These authors contributed equally: Mengjia He, Qianni Jin

Authors and Affiliations

  1. College of Clinical Medicine, Chongqing Medical University, 400016, Chongqing, China

    Mengjia He

  2. Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, 400016, Chongqing, China

    Qianni Jin, Yifeng Liu, Xiangsen Ye, Yulin Jiang, Feihu Ji, Husun Qian, Delu Gan, Shujun Yue & Tingmei Chen

  3. Department of Laboratory Medicine, Chongqing Medical University, 400016, Chongqing, China

    Qianni Jin, Yifeng Liu, Xiangsen Ye, Yulin Jiang, Feihu Ji, Husun Qian, Delu Gan, Shujun Yue & Tingmei Chen

  4. Department of General Surgery, Zhongshan Hospital Affiliated to Fudan University, 200032, Shanghai, China

    Cong Chen & Wei Zhu

Authors
  1. Mengjia He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qianni Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yifeng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiangsen Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yulin Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Feihu Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Husun Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Delu Gan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shujun Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wei Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tingmei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Wei Zhu or Tingmei Chen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

He, M., Jin, Q., Chen, C. et al. The miR-186-3p/EREG axis orchestrates tamoxifen resistance and aerobic glycolysis in breast cancer cells. Oncogene 38, 5551–5565 (2019). https://doi.org/10.1038/s41388-019-0817-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-0817-3

This article is cited by

Search

Advanced search

Quick links