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.

  • Original Article
  • Published:

Beclin 1 regulates growth factor receptor signaling in breast cancer

Oncogene volume 34, pages 5352–5362 (2015)Cite this article

Subjects

Abstract

Beclin 1 is a haploinsufficient tumor suppressor that is decreased in many human tumors. The function of beclin 1 in cancer has been attributed primarily to its role in the degradative process of macroautophagy. However, beclin 1 is a core component of the vacuolar protein sorting 34 (Vps34)/class III phosphatidylinositoI-3 kinase (PI3KC3) and Vps15/p150 complex that regulates multiple membrane-trafficking events. In the current study, we describe an alternative mechanism of action for beclin 1 in breast cancer involving its control of growth factor receptor signaling. We identify a specific stage of early endosome maturation that is regulated by beclin 1, the transition of APPL1-containing phosphatidyIinositol 3-phosphate-negative (PI3P−) endosomes to PI3P+ endosomes. Beclin 1 regulates PI3P production in response to growth factor stimulation to control the residency time of growth factor receptors in the PI3P−/APPL+-signaling-competent compartment. As a result, suppression of BECN1 sustains growth factor-stimulated AKT and ERK activation resulting in increased breast carcinoma cell invasion. In human breast tumors, beclin 1 expression is inversely correlated with AKT and ERK phosphorylation. Our data identify a novel role for beclin 1 in regulating growth factor signaling and reveal a mechanism by which loss of beclin 1 expression would enhance breast cancer progression.

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Seaman MN, Marcusson EG, Cereghino JL, Emr SD . Endosome to Golgi retrieval of the vacuolar protein sorting receptor, Vps10p, requires the function of the VPS29, VPS30, and VPS35 gene products. J Cell Biol 1997; 137: 79–92.

    Article  CAS  Google Scholar 

  2. Kametaka S, Okano T, Ohsumi M, Ohsumi Y . Apg14p and Apg6/Vps30p form a protein complex essential for autophagy in the yeast, Saccharomyces cerevisiae. J Biol Chem 1998; 273: 22284–22291.

    Article  CAS  Google Scholar 

  3. Yue Z, Jin S, Yang C, Levine AJ, Heintz N . Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 2003; 100: 15077–15082.

    Article  CAS  Google Scholar 

  4. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 2003; 112: 1809–1820.

    Article  CAS  Google Scholar 

  5. Cicchini M, Chakrabarti R, Kongara S, Price S, Nahar R, Lozy F et al. Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity. Autophagy 2014; 10: 2036–5.

    Article  Google Scholar 

  6. Li Z, Chen B, Wu Y, Jin F, Xia Y, Liu X . Genetic and epigenetic silencing of the beclin 1 gene in sporadic breast tumors. BMC Cancer 2010; 10: 98.

    Article  Google Scholar 

  7. Laddha SV, Ganesan S, Chan CS, White E . Mutational landscape of the essential autophagy gene BECN1 in human cancers. Mol Cancer Res 2014; 12: 485–490.

    Article  CAS  Google Scholar 

  8. Dong M, Wan X-B, Yuan ZY, Wei L, Fan XJ, Wang T-T et al. Low expression of Beclin 1 and elevated expression of HIF-1α refine distant metastasis risk and predict poor prognosis of ER-positive, HER2-negative breast cancer. Med Oncol 2013; 30: 355.

    Article  Google Scholar 

  9. Wang J, Pan X-L, Ding L-J, Liu D-Y, Lei D-P, Jin T . Aberrant expression of Beclin-1 and LC3 correlates with poor prognosis of human hypopharyngeal squamous cell carcinoma. PLoS ONE 2013; 8: e69038.

    Article  CAS  Google Scholar 

  10. Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev 2007; 21: 1621–1635.

    Article  CAS  Google Scholar 

  11. Schu PV, Takegawa K, Fry MJ, Stack JH, Waterfield MD, Emr SD . Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science 1993; 260: 88–91.

    Article  CAS  Google Scholar 

  12. Stephens L, Cooke FT, Walters R, Jackson T, Volinia S, Gout I et al. Characterization of a phosphatidylinositol-specific phosphoinositide 3-kinase from mammalian cells. Curr Biol 1994; 4: 203–214.

    Article  CAS  Google Scholar 

  13. Gaullier JM, Simonsen A, D'Arrigo A, Bremnes B, Stenmark H, Aasland R . FYVE fingers bind PtdInsP. Nature 1998; 394: 432–433.

    Article  CAS  Google Scholar 

  14. Patki V, Lawe DC, Corvera S, Virbasius JV, Chawla A . A functional PtdInsP-binding motif. Nature 1998; 394: 433–434.

    Article  CAS  Google Scholar 

  15. Lindmo K, Stenmark H . Regulation of membrane traffic by phosphoinositide 3-kinases. J Cell Sci 2006; 119 (Pt 4): 605–614.

    Article  CAS  Google Scholar 

  16. Kihara A, Noda T, Ishihara N, Ohsumi Y . Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol 2001; 152: 519–530.

    Article  CAS  Google Scholar 

  17. Itakura E, Kishi C, Inoue K, Mizushima N . Beclin 1 forms two distinct phosphatidylinositol 3-kinase complexes with mammalian Atg14 and UVRAG. Mol Biol Cell 2008; 19: 5360–5372.

    Article  CAS  Google Scholar 

  18. Law JH, Habibi G, Hu K, Masoudi H, Wang MYC, Stratford AL et al. Phosphorylated insulin-like growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 2008; 68: 10238–10246.

    Article  CAS  Google Scholar 

  19. Resnik JL, Reichart DB, Huey K, Webster NJ, Seely BL . Elevated insulin-like growth factor I receptor autophosphorylation and kinase activity in human breast cancer. Cancer Res 1998; 58: 1159–1164.

    CAS  Google Scholar 

  20. Park HS, Jang MH, Kim EJ, Kim HJ, Lee HJ, Kim YJ et al. High EGFR gene copy number predicts poor outcome in triple-negative breast cancer. Mod Pathol 2014; 27: 1212–1222.

    Article  CAS  Google Scholar 

  21. Miaczynska M, Pelkmans L, Zerial M . Not just a sink: endosomes in control of signal transduction. Curr Opin Cell Biol 2004; 16: 400–406.

    Article  CAS  Google Scholar 

  22. Dutta D, Donaldson JG . Search for inhibitors of endocytosis: intended specificity and unintended consequences. Cell Logist 2012; 2: 203–208.

    Article  Google Scholar 

  23. Platta HW, Stenmark H . Endocytosis and signaling. Curr Opin Cell Biol 2011; 23: 393–403.

    Article  CAS  Google Scholar 

  24. Hayakawa A, Leonard D, Murphy S, Hayes S, Soto M, Fogarty K et al. The WD40 and FYVE domain containing protein 2 defines a class of early endosomes necessary for endocytosis. Proc Natl Acad Sci USA 2006; 103: 11928–11933.

    Article  CAS  Google Scholar 

  25. Zoncu R, Perera RM, Balkin DM, Pirruccello M, Toomre D, De Camilli P . A phosphoinositide switch controls the maturation and signaling properties of APPL endosomes. Cell 2009; 136: 1110–1121.

    Article  CAS  Google Scholar 

  26. Schenck A, Goto-Silva L, Collinet C, Rhinn M, Giner A, Habermann B et al. The endosomal protein Appl1 mediates Akt substrate specificity and cell survival in vertebrate development. Cell 2008; 133: 486–497.

    Article  CAS  Google Scholar 

  27. Mitsuuchi Y, Johnson SW, Sonoda G, Tanno S, Golemis EA, Testa JR . Identification of a chromosome 3p14. 3-21.1 gene, APPL, encoding an adaptor molecule that interacts with the oncoprotein-serine/threonine kinase AKT2. Oncogene 1999; 18: 4891.

    Article  CAS  Google Scholar 

  28. Lee M-H, Klein RL, El-Shewy HM, Luttrell DK, Luttrell LM . The adiponectin receptors AdipoR1 and AdipoR2 activate ERK1/2 through a Src/Ras-dependent pathway and stimulate cell growth. Biochemistry 2008; 47: 11682–11692.

    Article  CAS  Google Scholar 

  29. Jones RB, Gordus A, Krall JA, MacBeath G . A quantitative protein interaction network for the ErbB receptors using protein microarrays. Nature 2006; 439: 168–174.

    Article  CAS  Google Scholar 

  30. Ryu J, Galan AK, Xin X, Dong F, Abdul-Ghani MA, Zhou L et al. APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor. Cell Rep 2014; 7: 1227–1238.

    Article  CAS  Google Scholar 

  31. Shravage BV, Hill JH, Powers CM, Wu L, Baehrecke EH . Atg6 is required for multiple vesicle trafficking pathways and hematopoiesis in Drosophila. Development 2013; 140: 1321–1329.

    Article  CAS  Google Scholar 

  32. Kametaka S, Matsuura A, Wada Y, Ohsumi Y . Structural and functional analyses of APG5, a gene involved in autophagy in yeast. Gene 1996; 178: 139–143.

    Article  CAS  Google Scholar 

  33. Leonard D, Hayakawa A, Lawe D, Lambright D, Bellvé KD, Standley C et al. Sorting of EGF and transferrin at the plasma membrane and by cargo-specific signaling to EEA1-enriched endosomes. J Cell Sci 2008; 121 (Pt 20): 3445–3458.

    Article  CAS  Google Scholar 

  34. Dillon RL, Marcotte R, Hennessy BT, Woodgett JR, Mills GB, Muller WJ . Akt1 and akt2 play distinct roles in the initiation and metastatic phases of mammary tumor progression. Cancer Res 2009; 69: 5057–5064.

    Article  CAS  Google Scholar 

  35. Arboleda MJ, Lyons JF, Kabbinavar FF, Bray MR, Snow BE, Ayala R et al. Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Cancer Res 2003; 63: 196–206.

    CAS  Google Scholar 

  36. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013; 6: pl1.

    Article  Google Scholar 

  37. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012; 2: 401–404.

    Article  Google Scholar 

  38. Lőrincz P, Lakatos Z, Maruzs T, Szatmári Z, Kis V, Sass M . Atg6/UVRAG/Vps34-containing lipid kinase complex is required for receptor downregulation through endolysosomal degradation and epithelial polarity during Drosophila wing development. Biomed Res Int 2014; 2014: 851349.

    Article  Google Scholar 

  39. Lawe DC, Chawla A, Merithew E, Dumas J, Carrington W, Fogarty K et al. Sequential roles for phosphatidylinositol 3-phosphate and Rab5 in tethering and fusion of early endosomes via their interaction with EEA1. J Biol Chem 2002; 277: 8611–8617.

    Article  CAS  Google Scholar 

  40. Er EE, Mendoza MC, Mackey AM, Rameh LE, Blenis J . AKT facilitates EGFR trafficking and degradation by phosphorylating and activating PIKfyve. Sci Signal 2013; 6: ra45.

    Article  Google Scholar 

  41. Liang C, Feng P, Ku B, Dotan I, Canaani D, Oh B-H et al. Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat Cell Biol 2006; 8: 688–699.

    Article  CAS  Google Scholar 

  42. Knævelsrud H, Ahlquist T, Merok MA, Nesbakken A, Stenmark H, Lothe RA et al. UVRAG mutations associated with microsatellite unstable colon cancer do not affect autophagy. Autophagy 2010; 6: 863–870.

    Article  Google Scholar 

  43. Liang C, Lee J-S, Inn K-S, Gack MU, Li Q, Roberts EA et al. Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol 2008; 10: 776–787.

    Article  CAS  Google Scholar 

  44. Wei Y, Zou Z, Becker N, Anderson M, Sumpter R, Xiao G et al. EGFR-mediated Beclin 1 phosphorylation in autophagy suppression, tumor progression, and tumor chemoresistance. Cell 2013; 154: 1269–1284.

    Article  CAS  Google Scholar 

  45. Wang RC, Wei Y, An Z, Zou Z, Xiao G, Bhagat G et al. Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 2012; 338: 956–959.

    Article  CAS  Google Scholar 

  46. Navaroli DM, Bellvé KD, Standley C, Lifshitz LM, Cardia J, Lambright D et al. Rabenosyn-5 defines the fate of the transferrin receptor following clathrin-mediated endocytosis. Proc Natl Acad Sci 2012; 109: E471–E480.

    Article  CAS  Google Scholar 

  47. Hayakawa A, Hayes SJ, Lawe DC, Sudharshan E, Tuft R, Fogarty K et al. Structural basis for endosomal targeting by FYVE domains. J Biol Chem 2004; 279: 5958–5966.

    Article  CAS  Google Scholar 

  48. Pankratz SL, Tan EY, Fine Y, Mercurio AM, Shaw LM . Insulin receptor substrate-2 regulates aerobic glycolysis in mouse mammary tumor cells via glucose transporter 1. J Biol Chem 2008; 284: 2031–2037.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institute of Health (NIH) grants CA142782 and CA177167 (LMS), DK60564 (SC) and CA159314 (EHB). We thank Lawrence M Lifshitz and Clive Standley of the UMass Biomedical Imaging Group for their contributions to the programs used to analyze the TESM data. We thank Sha Zhu for assistance with cloning, Usha Acharya for assistance with the PI3P lipid measurements and Chung-Cheng Hsieh for statistical advice.

Author information

Authors and Affiliations

  1. Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA

    R A Rohatgi, J Janusis, E H Baehrecke & L M Shaw

  2. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    D Leonard & S Corvera

  3. Biomedical Imaging Group, University of Massachusetts Medical School, Worcester, MA, USA

    K D Bellvé & K E Fogarty

Authors
  1. R A Rohatgi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Janusis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Leonard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K D Bellvé
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K E Fogarty
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E H Baehrecke
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Corvera
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L M Shaw
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L M Shaw.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rohatgi, R., Janusis, J., Leonard, D. et al. Beclin 1 regulates growth factor receptor signaling in breast cancer. Oncogene 34, 5352–5362 (2015). https://doi.org/10.1038/onc.2014.454

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.454

This article is cited by

Search

Advanced search

Quick links