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Ethanol enhances erbB-mediated migration of human breast cancer cells in culture

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Abstract

Growth factor systems (ligands and their receptors) are targets of ethanol toxicity. Inasmuch as alcohol consumption may increase the risk and development of breast cancer, we hypothesize that ethanol enhances cell migration by up-regulating the activities of erbB receptors. Of the three tested breast cancer cell lines that exhibit low invasion capacity (BT-20, MCF-7, and T47D cells), erbB receptors were specifically affected by ethanol only in the T47D cells. Ethanol increased erbB2, erbB3, and erbB4 expression in T47D human breast cancer cells in a concentration-dependent manner. ErbB1 (epidermal growth factor receptor) was unaffected. Heregulin β1 (ligand for erbB3 and erbB4) induced a modest increase in the invasion potential of the T47D cells. Ethanol alone also promoted modest invasion by the T47D cells, however, ethanol dramatically increased their heregulin-mediated invasion. Knocking-out erbB2 with an anti-sense oligonucleotide eliminated heregulin β1-promoted migration and blocked ethanol-induced chemo-migration. Thus, these data suggest that alcohol may enhance metastasis by altering an erbB system, and pivotally, erbB2.

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References

  1. IARC: Monographs on the evaluation of carcinogenic risk of chemicals to humans. Tobacco Smoking. Vol. 38. IARC Lyon, 1986

    Google Scholar 

  2. Tønnesen H, Moller H, Andersen JR, Jensen E, Juel K: Cancer morbidity in alcohol abusers. Brit J Cancer 69: 327-332, 1994

    Google Scholar 

  3. Smith-Warner SA, Spiegelman D, Yaun SS, Vandenbrandt PA, Folsom AR, Goldbohm RA, Graham S, Holmberg L, Howe GR, Marshall JR, Miller AB, Potter JD, Speizer FE, Willett WC, Wolk A, Hunter DJ: Alcohol and breast cancer in women - a pooled analysis of cohort studies. J Am Med Assoc 279: 535-540, 1998

    Google Scholar 

  4. NIAAA: Alcohol Alert No. 46, 1999

  5. Hiatt R: Alcohol consumption and breast cancer. Med Oncol Tumor Pharmacother 7: 143-151, 1990

    Google Scholar 

  6. Kelsey J, Horn-Ross PL: Breast cancer: magnitude of the problem and descriptive epidemiology. Epidemiol Rev 15: 7-16, 1993

    Google Scholar 

  7. Longnecker M: Alcohol beverage consumption in relation to risk of breast cancer: meta-analysis and review. Cancer Causes Control 5: 73-82, 1994

    Google Scholar 

  8. Plant ML: Alcohol and breast cancer: a review. Intl J Addict 27: 107-128, 1992

    Google Scholar 

  9. Rosenberg L, Metzger LS, Palmer JR: Alcohol consumption and risk of breast cancer: a review of the epidemiologic evidence. Epidemiol Rev 15: 133-144, 1993

    Google Scholar 

  10. William RR, Horm JW: Association of cancer sites with tobacco and alcohol consumption and socioeconomic status of patient: interview study from Third National Cancer Survey. J Natl Cancer Inst 58: 525-547, 1997

    Google Scholar 

  11. Bowlin SJ, Leske MC, Varma A, Nasca P, Weinstein, Caplan L: Breast cancer risk and alcohol consumption: results from a large case-control study. Intl J Epidemiol 26: 915-923, 1997

    Google Scholar 

  12. Swanson CA, Coates RJ, Malone KE, Gammon MD, Schoenberg JB, Brogan DJ, McAdams M, Potischman N, Hoover RN, Brinton LA: Alcohol consumption and breast cancer risk among women under age 45 years. Epidemiology 8: 231-237, 1997

    Google Scholar 

  13. Vaeth PAC, Satariano WA: Alcohol consumption and breast cancer stage at diagnosis. Alcohol Clin Exp Res 22: 928-934, 1998

    Google Scholar 

  14. Weiss HA, Brinton LA, Brogan D, Coates RJ, Gammon MD, Malone KE, Schoenberg JB, Swanson CA: Epidemiology of in situ and invasive breast cancer in women aged under 45. Brit J Cancer 73: 1298-1305, 1996

    Google Scholar 

  15. Baselga J, Mendelsohn J: Receptor blockade with monoclonal antibodies as anti-cancer therapy. Pharmacol Ther 64: 127-154, 1994

    Google Scholar 

  16. Cohen BD, Siegall CB, Bacus S, Foy L, Green JM, Hellstrom I, Hellstrom KE, Fell HP: Role of epidermal growth factor receptor family members in growth and differentiation of breast carcinoma. Biochem Soc Symp 63: 199-210, 1998

    Google Scholar 

  17. Harris JR, Lippman ME, Veronesi U, Willett W: Breast cancer. New Engl J Med 327: 473-480, 1992

    Google Scholar 

  18. Hynes NE: Amplification and overexpression of erbB-2 gene in human tumors: its involvement in tumor development, significance as a prognostic factor, and potential as a target for cancer therapy. Sem Cancer Biol 4: 19-26, 1993

    Google Scholar 

  19. Hynes NE, Stern DE: The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta 1198: 165-184, 1994

    Google Scholar 

  20. Lupu R, Cardillo M, Harris L, Hijazi M, Rosenberg K: Interaction between erbB-receptors and heregulin in breast cancer tumor progression and drug resistance. Sem Cancer Biol 6: 135-145, 1995

    Google Scholar 

  21. Prigent SA, Lemoine NR: The type 1 (EGFR-related) family of growth factor receptors and their ligands. Prog Growth Factor Res 4: 1-24, 1992

    Google Scholar 

  22. Gullick WJ: Type I growth factor receptors: current status and future work. Biochem Soc Symp 63: 193-198, 1998

    Google Scholar 

  23. Berchuck A, Kamel A, Whitaker R, Kerns B, Olt G, Kinney R, Soper JT, Dodge R, Clarke-Pearson DL, Marks P, McKenzie S, Yin S, Bast RC Jr: Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res 50: 4087-4091, 1990

    Google Scholar 

  24. Maguire HC, Greene MI: The neu (c-erbB-2) oncogene. Sem Oncol 16, 148-155, 1989

    Google Scholar 

  25. Reese DM, Slamon DJ: HER-2/neu signal transduction in human breast and ovarian cancer. Stem Cells 15: 1-8, 1997

    Google Scholar 

  26. Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich, A, Press MF: Studies of HER-2/neu protooncogene in human breast and ovarian cancer. Science 244: 707-712, 1989

    Google Scholar 

  27. Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ: Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 89: 10578-10582, 1992

    Google Scholar 

  28. Lupu R, Cardillo M, Cho C, Harris L, Hijazi M, Perez C, Rosenberg K, Yang D, Tang C: The significance of heregulin in breast cancer tumor progression and drug resistance. Breast Cancer Res Treat 38: 57-66, 1996

    Google Scholar 

  29. Xu F-J, Stack S, Boyer C, O'Briant K, Whitaker R, Mills GB, Yu YH, Bast RC Jr: Heregulin and agonsitic anti-p185c-erbB2 antibodies inhibit proliferation but increase invasiveness of breast cancer cells that over express p185c-erbB2; increased invasiveness may contribute to poor prognosis. Clin Cancer Res 3: 1629-1634, 1997

    Google Scholar 

  30. Luo J, Miller MW: Growth factor-mediated neural proliferation: target of ethanol toxicity. Brain Res Rev 27: 157-167, 1998

    Google Scholar 

  31. Adickes ED, Mollner TJ, Lockwood SK: Closed chamber system for delivery of ethanol to cell cultures. Alcohol Alcohol 23: 377-381, 1988

    Google Scholar 

  32. Luo J, Miller MW: Ethanol inhibits bFGF-mediated proliferation of C6 glioma cells. J Neurochem 67: 1448-1456, 1996

    Google Scholar 

  33. Luo J, Miller MW: Effects of ethanol on the expression of cerbB proteins and heregulin-mediated MAP kinase activity in human breast cancer cells. Alcohol Clin Exp Res 22: 111A, 1998

    Google Scholar 

  34. Pantazis NJ, Dohrman DP, Luo J, Goodlett CR, West JR: Alcohol reduces the number of pheochromocytoma (PC 12) cells in culture. Alcohol 9: 171-180, 1992

    Google Scholar 

  35. Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248-254, 1976

    Google Scholar 

  36. Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680-685, 1970

    Google Scholar 

  37. Luo J, Miller MW: Differential sensitivity of human neuroblastoma cells lines to ethanol: correlation with their proliferative responses to growth factors and expression of growth factor receptors. Alcohol Clin Exp Res 21: 1186-1194, 1997

    Google Scholar 

  38. Towbin H, Staehelin T, Gordon J: Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA 76: 4350-4354, 1979

    Google Scholar 

  39. Carraway KL III, Slikowski MX, Akita R, Platko JV, Guy PM, Nuijens A, Diamonti AJ, Vandlen RL, Cantley LC, Cerione RA: The erbB3 gene product is a receptor for heregulin. J Biol Chem 269: 14303-14306, 1994

    Google Scholar 

  40. Kuhn PE, Miller MW: Developmental expression of c-neu proteins in cerebral cortex: relationship to epidermal growth factor receptor. J Comp Neurol 372: 189-203, 1996

    Google Scholar 

  41. Lewis GD, Lofgren JA, McMurtrey AE, Nuijens A, Fendly BM, Bauer KD, Slikowski MX: Growth regulation of human breast and ovarian tumor cells by heregulin: evidence for the requirement of ErbB2 as a critical component in mediating heregulin responsiveness. Cancer Res 56: 1457-1465, 1996

    Google Scholar 

  42. Peles E, Ben-Levy R, Tzahar E, Liu N, Wen D, Yarden Y: Cell-type specific interaction of neu differentiation factor (NDF/heregulin) with neu/HER-2 suggests complex ligandreceptor relationships. EMBO J 12: 961-971, 1993

    Google Scholar 

  43. Sliwkowski MX, Schaefer G, Akita RW, Lofgren JA, Fitzpatrick VD, Nuijens A, Fendly BM, Cerione RA, Vandlen RL, Carraway KL III: Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem 269: 14661-14665, 1994

    Google Scholar 

  44. Colomer R, Lupu R, Bacus SS, Gelmann EP: ErbB-2 antisense oligonucleotides inhibit the proliferation of breast carcinoma cells with erbB-2 oncogene amplification. Brit J Cancer 70: 819-825, 1994

    Google Scholar 

  45. Hendrix MJC, Seftor EA, Seftor REB, Fidler IJ: A simple quantitative assay for studying the invasive potential of high and low human metastatic variants. Cancer Lett 38: 137-147, 1987

    Google Scholar 

  46. Melchiori A, Albini A, Ray JM, Stelter-Stevenson WG: Inhibition of tumor cell invasion by a highly conserved peptide sequence from the matrix metalloproteinase enzyme prosegment. Cancer Res 52: 2353-2356, 1992

    Google Scholar 

  47. Keydar I, Chen L, Karby S, Weiss FR, Delarea J, Radu M, Chaitcik S, Brenner HJ: Establishment and characterization of a cell line of human breast carcinoma origin. Eur J Cancer 15: 659-670, 1979

    Google Scholar 

  48. Kirschmann DA, Seftor EA, Nieva DRC, Mariano EA, Hendrix MJC: Differentially expressed genes associated with the metastatic phenotype in breast cancer. Breast Cancer Res Treat 55: 127-136, 1999

    Google Scholar 

  49. Klemke RL, Leng J, Molander R, Brooks PC, Vuori K, Cheresh DA: CAS/Crk coupling serves as a 'molecular switch' for induction of cell migration. J Cell Biol 140: 961-972, 1998

    Google Scholar 

  50. Thompson EW, Paik S, Brünner N, Sommers CL, Zugmaier G, Clarke G, Shima TB, Torri J, Donahue S, Lippman ME, Martin GR, Dickson RB: Association of increased basement membrane invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines. J Cell Physiol 150: 534-544, 1992

    Google Scholar 

  51. Henderson GI, Baskin GS, Horbach J, Porter P, Schenker S: Arrest of epidermal growth factor-dependent growth in fetal hepatocytes after ethanol exposure. J Clin Invest 84: 1287-1294, 1989

    Google Scholar 

  52. Wang SL, Jacober L, Wu-Wang CY, Slomiany A, Slomiany BL: Ethanol-induced structural and functional alteration of epidermal growth factor receptor in buccal mucosa. Intl J Biochem 24: 85-90, 1992

    Google Scholar 

  53. Burden S, Yarden Y: Neuregulins and their receptors: a versatile signal module in organogenesis and oncogenesis. Neuron 18: 847-855, 1997

    Google Scholar 

  54. Muller WJ, Sinn E, Pattengale PK, Wallace R, Leder P: Induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54: 105-115, 1988

    Google Scholar 

  55. Plowman GD, Green JM, Culouscou J-M, Carlton GW, Rothwell VM, Buckley S: Heregulin induces tyrosine phosphorylation of HER4/p180erbB4. Nature 366: 473-475, 1993

    Google Scholar 

  56. Zhang K, Sun J, Liu N, Wen D, Chang D, Thomason A, Yoshinaga SK: Transformation of NIH 3T3 cells by HER3 or HER4 receptors requires the presence of HER1 or HER2. J Biol Chem 271: 3884-3890, 1996

    Google Scholar 

  57. Alimandi M, Romano A, Curia MC, Muraro R, Fedi P, Aaronson SA, Di Fiore PP, Kraus MH: Cooperative signaling of erbB3 and erbB2 in neoplastic transformation and human mammary carcinomas. Oncogene 10: 1813-1821, 1995

    Google Scholar 

  58. Alroy I, Yarden Y: The erbB signaling network in embryogenesis and oncogenesis: signal diversification through combinatorial ligand-receptor interactions. FEBS Lett 410: 83-86, 1997

    Google Scholar 

  59. Carraway KI III, Cantley LC: A neu acquaintance for erbB3 and erbB4: a role for receptor heterodimerization in growth signaling. Cell 78: 5-8, 1994

    Google Scholar 

  60. Peles E, Bacus SS, Koski RA, Lu HS, Wen D, Ogden SG, Levy RB, Yarden Y: Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells. Cell 69: 205-216, 1992

    Google Scholar 

  61. Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, Yansura D, Abadi N, Raab H, Lewis GD, Shepard HM, Kuang W-J, Wood WI, Goeddel DV, Vandle RL: Identification of heregulin, a specific activator of p185erbB2. Science 256: 1205-1210, 1992

    Google Scholar 

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Authors and Affiliations

  1. Department of Psychiatry, University of Iowa College of Medicine, Iowa City, IA, USA

    Jia Luo & Michael W. Miller

  2. Research Service, Veterans Affairs Medical Center, Iowa City, IA, USA

    Michael W. Miller

  3. Department of Pharmacology, University of Iowa College of Medicine, Iowa City, IA, USA

    Michael W. Miller

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Luo, J., Miller, M.W. Ethanol enhances erbB-mediated migration of human breast cancer cells in culture. Breast Cancer Res Treat 63, 61–69 (2000). https://doi.org/10.1023/A:1006436315284

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