Breast Cancer Research and Treatment

, Volume 133, Issue 3, pp 1037–1048 | Cite as

Ethanol promotes mammary tumor growth and angiogenesis: the involvement of chemoattractant factor MCP-1

  • Siying Wang
  • Mei Xu
  • Feifei Li
  • Xin Wang
  • Kimberly A. Bower
  • Jacqueline A. Frank
  • Yanmin Lu
  • Gang Chen
  • Zhuo Zhang
  • Zunji Ke
  • Xianglin Shi
  • Jia Luo
Preclinical Study


Alcohol consumption is a risk factor for breast cancer in humans. Experimental studies indicate that alcohol exposure promotes malignant progression of mammary tumors. However, the underlying cellular and molecular mechanisms remain unclear. Alcohol induces a pro-inflammatory response by modulating the expression of cytokines and chemokines. Monocyte chemoattractant protein-1 (MCP-1), also known as chemokine (C–C motif) ligand 2, is a pro-inflammatory chemokine implicated in breast cancer development/malignancy. We investigated the role of MCP-1 in alcohol-promoted mammary tumor progression. Using a xenograft model, we demonstrated that alcohol increased tumor angiogenesis and promoted growth/metastasis of breast cancer cells in C57BL/6 mice. Alcohol up-regulated the expression of MCP-1 and its receptor CCR2 in breast cancer cells in vitro and in vivo. Using a three-dimensional tumor/endothelial cell co-culture system, we demonstrated MCP-1 regulated tumor/endothelial cell interaction and promoted tumor angiogenesis. More importantly, MCP-1 mediated alcohol-promoted angiogenesis; an antagonist of the MCP-1 receptor CCR2 significantly inhibited alcohol-stimulated tumor angiogenesis. The CCR2 antagonist abolished ethanol-stimulated growth of mammary tumors in mice. We further demonstrated that MCP-1 enhanced the migration, but not the proliferation of endothelial cells as well as breast cancer cells. These results suggest that MCP-1 plays an important role in ethanol-stimulated tumor angiogenesis and tumor progression.


Alcohol Angiogenesis Chemokines Metastasis Migration 



Average microvessel density


Chemokine (C–C motif) ligand 2


CC chemokine receptor 2


CCR2 antagonist


Monocyte chemoattractant protein-1



This research is supported by grants from National Institute of Health (AA017226 and AA015407).

Conflict of interest

The authors declare that they have no conflict of interests.


  1. 1.
    ACS (2009) In: Breast cancer facts and figures 2009–2010. American Cancer Society, Atlanta, pp 1–36Google Scholar
  2. 2.
    Key J, Hodgson S, Omar RZ, Jensen TK, Thompson SG, Boobis AR, Davies DS, Elliott P (2006) Meta-analysis of studies of alcohol and breast cancer with consideration of the methodological issues. Cancer Causes Control 17:759–770PubMedCrossRefGoogle Scholar
  3. 3.
    Seitz HK, Becker P (2007) Alcohol metabolism and cancer risk. Alcohol Res Health 30:37–38Google Scholar
  4. 4.
    Seitz HK, Maurer B (2007) The relationship between alcohol metabolism, estrogen levels, and breast cancer risk. Alcohol Res Health 30:42–43PubMedGoogle Scholar
  5. 5.
    Singletary KW, Gapstur SM (2001) Alcohol and breast cancer: review of epidemiologic and experimental evidence and potential mechanisms. JAMA 286:2143–2151PubMedCrossRefGoogle Scholar
  6. 6.
    Tjonneland A, Christensen J, Olsen A, Stripp C, Thomsen BL, Overvad K et al (2007) Alcohol intake and breast cancer risk: the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes Control 18:361–373PubMedCrossRefGoogle Scholar
  7. 7.
    Visvanathan K, Crum RM, Strickland PT, You X, Ruczinski I, Berndt SI, Alberg AJ, Hoffman SC, Comstock GW, Bell DA, Helzlsouer KJ (2007) Alcohol dehydrogenase genetic polymorphisms, low-to-moderate alcohol consumption, and risk of breast cancer. Alcohol Clin Exp Res 31:467–476PubMedCrossRefGoogle Scholar
  8. 8.
    Stoll BA (1999) Alcohol intake and late-stage promotion of breast cancer. Eur J Cancer 35:1653–1658PubMedCrossRefGoogle Scholar
  9. 9.
    Vaeth PA, Satariano WA (1998) Alcohol consumption and breast cancer stage at diagnosis. Alcohol Clin Exp Res 22:928–934PubMedCrossRefGoogle Scholar
  10. 10.
    Weiss HA, Brinton LA, Brogan D, Coates RJ, Gammon MD, Malone KE, Schoenberg JB, Swanson CA (1996) Epidemiology of in situ and invasive breast cancer in women aged under 45. Br J Cancer 73:1298–1305PubMedCrossRefGoogle Scholar
  11. 11.
    Bonecchi R, Galliera E, Borroni EM, Corsi MM, Locati M, Mantovani A (2009) Chemokines and chemokine receptors: an overview. Front Biosci 14:540–551PubMedCrossRefGoogle Scholar
  12. 12.
    Craig MJ, Loberg RD (2006) CCL2 (monocyte chemoattractant protein-1) in cancer bone metastases. Cancer Metastasis Rev 25:611–619PubMedCrossRefGoogle Scholar
  13. 13.
    Soria G, Ben-Baruch A (2008) The inflammatory chemokines CCL2 and CCL5 in breast cancer. Cancer Lett 267:271–285PubMedCrossRefGoogle Scholar
  14. 14.
    Mandrekar P, Szabo G (2009) Signalling pathways in alcohol-induced liver inflammation. J Hepatol 50:1258–1266PubMedCrossRefGoogle Scholar
  15. 15.
    Wang HJ, Zakhari S, Jung MK (2010) Alcohol, inflammation, and gut-liver-brain interactions in tissue damage and disease development. World J Gastroenterol 16:1304–1313PubMedCrossRefGoogle Scholar
  16. 16.
    He J, Crews FT (2008) Increased MCP-1 and microglia in various regions of the human alcoholic brain. Exp Neurol 210:349–358PubMedCrossRefGoogle Scholar
  17. 17.
    Qin L, He J, Hanes RN, Pluzarev O, Hong JS, Crews FT (2008) Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment. J Neuroinflamm 5:10CrossRefGoogle Scholar
  18. 18.
    Ke Z, Wang X, Liu Y, Fan Z, Chen G, Xu M, Bower KA, Frank JA, Li M, Fang S, Shi X, Luo J (2011) Ethanol induces endoplasmic reticulum stress in the developing brain. Alcohol Clin Exp Res 35:1574–1583PubMedGoogle Scholar
  19. 19.
    Ewens A, Luo L, Berleth E, Alderfer J, Wollman R, Hafeez BB, Kanter P, Mihich E, Ehrke MJ (2006) Doxorubicin plus interleukin-2 chemoimmunotherapy against breast cancer in mice. Cancer Res 66:5419–5426PubMedCrossRefGoogle Scholar
  20. 20.
    Major TC, Olszewski B, Rosebury-Smith WS (2009) A CCR2/CCR5 antagonist attenuates an increase in angiotensin II-induced CD11b+ monocytes from atherogenic ApoE−/− mice. Cardiovasc Drugs Ther 23:113–120PubMedCrossRefGoogle Scholar
  21. 21.
    Liu Y, Chen G, Ma C, Bower KA, Xu M, Fan Z, Shi X, Ke ZJ, Luo J (2009) Overexpression of glycogen synthase kinase 3beta sensitizes neuronal cells to ethanol toxicity. J Neurosci Res 87:2793–2802PubMedCrossRefGoogle Scholar
  22. 22.
    Chen Z, Htay A, Dos Santos W, Gillies GT, Fillmore HL, Sholley MM, Broaddus WC (2009) In vitro angiogenesis by human umbilical vein endothelial cells (HUVEC) induced by three-dimensional co-culture with glioblastoma cells. J Neurooncol 92:121–128PubMedCrossRefGoogle Scholar
  23. 23.
    Luo J, Miller MW (1997) Differential sensitivity of human neuroblastoma cell lines to ethanol: correlations with their proliferative responses to mitogenic growth factors and expression of growth factor receptors. Alcohol Clin Exp Res 21:1186–1194PubMedGoogle Scholar
  24. 24.
    Xu M, Bower KA, Wang S, Frank JA, Chen G, Ding M, Wang S, Shi X, Ke Z, Luo J (2010) Cyanidin-3-glucoside inhibits ethanol-induced invasion of breast cancer cells overexpressing ErbB2. Mol Cancer 9:285PubMedCrossRefGoogle Scholar
  25. 25.
    Tan W, Bailey AP, Shparago M, Busby B, Covington J, Johnson JW, Young E, Gu JW (2007) Chronic alcohol consumption stimulates VEGF expression, tumor angiogenesis and progression of melanoma in mice. Cancer Biol Ther 6:1211–1217PubMedCrossRefGoogle Scholar
  26. 26.
    Zhong S, Machida K, Tsukamoto H, Johnson DL (2011) Alcohol induces RNA polymerase III-dependent transcription through c-Jun by co-regulating TATA-binding protein (TBP) and Brf1 expression. J Biol Chem 286:2393–2401PubMedCrossRefGoogle Scholar
  27. 27.
    Hong J, Holcomb VB, Tekle SA, Fan B, Núñez NP (2010) Alcohol consumption promotes mammary tumor growth and insulin sensitivity. Cancer Lett 294:229–235PubMedCrossRefGoogle Scholar
  28. 28.
    Yirmiya R, Ben-Eliyahu S, Gale RP, Shavit Y, Liebeskind JC, Taylor AN (1992) Ethanol increases tumor progression in rats: possible involvement of natural killer cells. Brain Behav Immun 6:74–86PubMedCrossRefGoogle Scholar
  29. 29.
    Gu JW, Elam J, Sartin A, Li W, Roach R, Adair TH (2001) Moderate levels of ethanol induce expression of vascular endothelial growth factor and stimulate angiogenesis. Am J Physiol Regul Integr Comp Physiol 281:R365–R372PubMedGoogle Scholar
  30. 30.
    Qian Y, Luo J, Leonard SS, Harris GK, Millecchia L, Flynn DC, Shi X (2003) Hydrogen peroxide formation and actin filament reorganization by Cdc42 are essential for ethanol-induced in vitro angiogenesis. J Biol Chem 278:16189–16197PubMedCrossRefGoogle Scholar
  31. 31.
    Melgarejo E, Medina MA, Sánchez-Jiménez F, Urdiales JL (2009) Monocyte chemoattractant protein-1: a key mediator in inflammatory processes. Int J Biochem Cell Biol 41:998–1001PubMedCrossRefGoogle Scholar
  32. 32.
    Raffaghello L, Cocco C, Corrias MV, Airoldi I, Pistoia V (2009) Chemokines in neuroectodermal tumour progression and metastasis. Semin Cancer Biol 19:97–102PubMedCrossRefGoogle Scholar
  33. 33.
    Zhang J, Patel L, Pienta KJ (2010) CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis. Cytokine Growth Factor Rev 21:41–48PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Siying Wang
    • 1
    • 2
  • Mei Xu
    • 1
  • Feifei Li
    • 2
  • Xin Wang
    • 3
  • Kimberly A. Bower
    • 1
  • Jacqueline A. Frank
    • 1
  • Yanmin Lu
    • 2
  • Gang Chen
    • 1
  • Zhuo Zhang
    • 3
  • Zunji Ke
    • 4
  • Xianglin Shi
    • 3
  • Jia Luo
    • 1
  1. 1.Department of Internal MedicineUniversity of Kentucky College of MedicineLexingtonUSA
  2. 2.Pathophysiological Department, School of Basic MedicineAnhui Medical UniversityHefeiChina
  3. 3.Graduate Center for ToxicologyUniversity of KentuckyLexingtonUSA
  4. 4.Institute for Nutritional Sciences, Shanghai Institutes for Biological SciencesChinese Academy of SciencesShanghaiChina

Personalised recommendations