Myoferlin is a key regulator of EGFR activity in breast cancer.

[en] Myoferlin is a member of the ferlin family of proteins that participate in plasma membrane fusion, repair and endocytosis. While some reports have implicated myoferlin in cancer, the extent of its expression in and contributions to cancer are not well established. In this study, we show that myoferlin is overexpressed in human breast cancers and that it is has a critical role in controlling degradation of the EGFR after its activation and internalization in breast cancer cells. Myoferlin depletion blocked EGF-induced cell migration and epithelial-to-mesenchymal transition. Both effects were induced as a result of impaired degradation of phosphorylated EGFR via dysfunctional plasma membrane caveolae and alteration of caveolin homooligomerization. In parallel, myoferlin depletion reduced tumor development in a chicken chorioallantoic membrane xenograft model of human breast cancer. Considering the therapeutic significance of EGFR targeting, our findings identify myoferlin as an novel candidate function to target for future drug development.

Disciplines :

Endocrinology, metabolism & nutrition
Biochemistry, biophysics & molecular biology
Radiology, nuclear medicine & imaging

Author, co-author :

Turtoi, Andrei ^✱; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases

Blomme, Arnaud ^✱; Université de Liège - ULiège > Doct. sc. bioméd. & pharma. (Bologne)

Bellahcene, Akeila ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases

Gilles, Christine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement

Hennequière, Vincent ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire

Peixoto, Paul ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases

BIANCHI, Elettra ; Centre Hospitalier Universitaire de Liège - CHU > Anatomie pathologique

Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme

De Pauw, Edwin ; Université de Liège - ULiège > Département de chimie (sciences) > GIGA-R : Laboratoire de spectrométrie de masse (L.S.M.)

LIFRANGE, Eric ; Centre Hospitalier Universitaire de Liège - CHU > Sénologie

Delvenne, Philippe ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques

Castronovo, Vincenzo ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie générale et cellulaire

^✱ These authors have contributed equally to this work.

Language :

English

Title :

Myoferlin is a key regulator of EGFR activity in breast cancer.

Publication date :

2013

Journal title :

Cancer Research

ISSN :

0008-5472

eISSN :

1538-7445

Publisher :

American Association for Cancer Research, Inc. (AACR), Baltimore, United States - Maryland

Volume :

Pages :

5438-5448

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 30 August 2013

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Bibliography

Yarden Y, Pines G. The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 2012;12:553-63.
Sigismund S, Woelk T, Puri C, Maspero E, Tacchetti C, Transidico P, et al. Clathrin-independent endocytosis of ubiquitinated cargos. Proc Natl Acad Sci U S A 2005;102:2760-5. (Pubitemid 40299866)
Sigismund S, Argenzio E, Tosoni D, Cavallaro E, Polo S, Di Fiore PP. Clathrin-mediated internalization is essential for sustained EGFR signaling but dispensable for degradation. Dev Cell 2008;15: 209-19.
Davis DB, Delmonte AJ, Ly CT, McNally EM. Myoferlin, a candidate gene and potential modifier of muscular dystrophy. Hum Mol Genet 2000;9:217-26. (Pubitemid 30052745)
Doherty KR, Demonbreun AR, Wallace GQ, Cave A, Posey AD, Heretis K, et al. The endocytic recycling protein EHD2 interacts with myoferlin to regulate myoblast fusion. J Biol Chem 2008;283:20252-60.
Posey AD Jr, Demonbreun A, McNally EM. Ferlin proteins in myoblast fusion and muscle growth. Curr Top Dev Biol 2011;96:203-30.
Martens S, McMahon HT. Mechanisms of membrane fusion: disparate players and common principles. Nat Rev Mol Cell Biol 2008; 9:543-56. (Pubitemid 351881838)
McNeil PL, Kirchhausen T. An emergency response team for membrane repair. Nat Rev Mol Cell Biol 2005;6:499-505. (Pubitemid 40780561)
Bernatchez PN, Sharma A, Kodaman P, Sessa WC. Myoferlin is critical for endocytosis in endothelial cells. Am J Physiol Cell Physiol 2009;297:C484-92.
Bernatchez PN, Acevedo L, Fernandez-Hernando C, Murata T, Chalouni C, Kim J, et al. Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function. J Biol Chem 2007;282: 30745-53. (Pubitemid 350035229)
Yu C, Sharma A, Trane A, Utokaparch S, Leung C, Bernatchez P. Myoferlin gene silencing decreases Tie-2 expression in vitro and angiogenesis in vivo. Vascul Pharmacol 2011;55:26-33.
Demonbreun AR, Posey AD, Heretis K, Swaggart KA, Earley JU, Pytel P, et al. Myoferlin is required for insulin-like growth factor response and muscle growth. FASEB J 2010;24:1284-95.
Eisenberg MC, Kim Y, Li R, Ackerman WE, Kniss DA, Friedman A. Mechanistic modeling of the effects of myoferlin on tumor cell invasion. Proc Natl Acad Sci U S A 2011;108:20078-83.
Li R, Ackerman WE, Mihai C, Volakis LI, Ghadiali S, Kniss DA. Myoferlin depletion in breast cancer cells promotes mesenchymal to epithelial shape change and stalls invasion. PLoS ONE 2012;7:e39766.
Leung C, Yu C, Lin MI, Tognon C, Bernatchez P. Expression of myoferlin in human and murine carcinoma tumors: role in membrane repair, cell proliferation, and tumorigenesis. Am J Pathol 2013;182: 1900-9.
Difilippantonio S, Chen Y, Pietas A, Schlüns K, Pacyna-Gengelbach M, Deutschmann N, et al. Gene expression profiles in human non-small and small-cell lung cancers. Eur J Cancer 2003;39:1936-47. (Pubitemid 37311192)
Abba MC, Hu Y, Sun H, Drake JA, Gaddis S, Baggerly K, et al. Gene expression signature of estrogen receptor alpha status in breast cancer. BMC Genomics 2005;6:37.
Turtoi A, Musmeci D, Wang Y, Dumont B, Somja J, Bevilacqua G, et al. Identification of novel accessible proteins bearing diagnostic and therapeutic potential in human pancreatic ductal adenocarcinoma. J Proteome Res 2011;10:4302-13.
Dumont B, Castronovo V, Peulen O, Blétard N, Clézardin P, Delvenne P, et al. Differential proteomic analysis of a human breast tumor and its matched bone metastasis identifies cell membrane and extracellular proteins associated with bone metastasis. J Proteome Res 2012;11: 2247-60.
Bonnomet A, Syne L, Brysse A, Feyereisen E, Thompson EW, Noël A, et al. A dynamic in vivo model of epithelial-to-mesenchymal transitions in circulating tumor cells and metastases of breast cancer. Oncogene 2012;31:3741-53.
Turtoi A, Dumont B, Greffe Y, Blomme A, Mazzucchelli G, Delvenne P, et al. Novel comprehensive approach for accessible biomarker identification and absolute quantification from precious human tissues. J Proteome Res 2011;10:3160-82.
Turtoi A, De Pauw E, Castronovo V. Innovative proteomics for the discovery of systemically accessible cancer biomarkers suitable for imaging and targeted therapies. Am J Pathol 2011;178: 12-8.
Grände M, Franzen A, Karlsson JO, Ericson LE, Heldin NE, Nilsson M. Transforming growth factor-beta and epidermal growth factor synergistically stimulate epithelial to mesenchymal transition (EMT) through a MEK-dependent mechanism in primary cultured pig thyrocytes. J Cell Sci 2002;115 (Pt 22):4227-36. (Pubitemid 35460694)
Lee MY, Chou CY, Tang MJ, Shen MR. Epithelial-mesenchymal transition in cervical cancer: correlation with tumor progression, epidermal growth factor receptor overexpression, and snail up-regulation. Clin Cancer Res 2008;14:4743-50.
Price JT, Tiganis T, Agarwal A, Djakiew D, Thompson EW. Epidermal growth factor promotes MDA-MB-231 breast cancer cell migration through a phosphatidylinositol 3'-kinase and phospholipase C-dependent mechanism. Cancer Res 1999;59:5475-8. (Pubitemid 29526460)
Parton RG, Simons K. The multiple faces of caveolae. Nat Rev Mol Cell Biol 2007;8:185-94.
Williams TM, Lisanti MP. Caveolin-1 in oncogenic transformation, cancer, and metastasis. Am J Physiol Cell Physiol 2005;288: C494-506. (Pubitemid 40229478)
Lajoie P, Partridge EA, Guay G, Goetz JG, Pawling J, Lagana A, et al. Plasma membrane domain organization regulates EGFR signaling in tumor cells. J Cell Biol 2007;179:341-56. (Pubitemid 350004897)
Li L, Yang G, Ebara S, Satoh T, Nasu Y, Timme TL, et al. Caveolin-1 mediates testosterone-stimulated survival/clonal growth and promotes metastatic activities in prostate cancer cells. Cancer Res 2001;61:4386-92. (Pubitemid 32685764)
Tahir SA, Yang G, Ebara S, Timme TL, Satoh T, Li L, et al. Secreted caveolin-1 stimulates cell survival/clonal growth and contributes to metastasis in androgen-insensitive prostate cancer. Cancer Res 2001; 61:3882-5. (Pubitemid 32720945)
Ho CC, Huang PH, Huang HY, Chen YH, Yang PC, Hsu SM. Upregulated caveolin-1 accentuates the metastasis capability of lung adenocarcinoma by inducing filopodia formation. Am J Pathol 2002; 161:1647-56.
Alwan HA, van Zoelen EJ, van Leeuwen JE. Ligand-induced lysosomal epidermal growth factor receptor (EGFR) degradation is preceded by proteasome-dependent EGFR de-ubiquitination. J Biol Chem 2003; 278:35781-90. (Pubitemid 37102355)
Longva KE, Blystad FD, Stang E, Larsen AM, Johannessen LE, Madshus IH. Ubiquitination and proteasomal activity is required for transport of the EGF receptor to inner membranes of multivesicular bodies. J Cell Biol 2002;156:843-54. (Pubitemid 34839867)
Roepstorff K, Grandal MV, Henriksen L, Knudsen SL, Lerdrup M, Grøvdal L, et al. Differential effects of EGFR ligands on endocytic sorting of the receptor. Traffic 2009;10:1115-27.
Schmidt-Glenewinkel H, Reinz E, Bulashevska S, Beaudouin J, Legewie S, Alonso A, et al. Multiparametric image analysis reveals role of Caveolin1 in endosomal progression rather than internalization of EGFR. FEBS Lett 2012;586:1179-89.
Sewing A, Wiseman B, Lloyd AC, Land H. High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1. Mol Cell Biol 1997; 17:5588-97. (Pubitemid 27357655)
Rush JS, Quinalty LM, Engelman L, Sherry DM, Ceresa BP. Endosomal accumulation of the activated epidermal growth factor receptor (EGFR) induces apoptosis. J Biol Chem 2012;287:712-22.
Ruth Li. The expression and effect of Myoferlin depletion in breast cancer cells [dissertation]. Columbus (OH): Ohio State University;2012.
Chakraborty J, Banerjee S, Ray P, Hossain DM, Bhattacharyya S, Adhikary A, et al. Gain of cellular adaptation due to prolonged p53 impairment leads to functional switchover from p53 to p73 during DNA damage in acute myeloid leukemia cells. J Biol Chem 2010;285: 33104-12.
Kok KH, Lei T, Jin DY. siRNA and shRNA screens advance key understanding of host factors required for HIV-1 replication. Retrovirology 2009;27:6-78.