Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2016

Open Access 01-12-2016 | Research

ErbB2 and p38γ MAPK mediate alcohol-induced increase in breast cancer stem cells and metastasis

Authors: Mei Xu, Zhenhua Ren, Xin Wang, Ashley Comer, Jacqueline A. Frank, Zun-ji Ke, Yi Huang, Zhuo Zhang, Xianglin Shi, Siying Wang, Jia Luo

Published in: Molecular Cancer | Issue 1/2016

Login to get access

Abstract

Background

Both epidemiological and experimental studies suggest that excessive alcohol exposure increases the risk for breast cancer and enhances metastasis/recurrence. We have previously demonstrated that alcohol enhanced the migration/invasion of breast cancer cells and cancer cells overexpressing ErbB2/HER2 were more sensitive to alcohol exposure. However, the underlying mechanisms remain unclear. This study was designed to investigate the mechanisms underlying alcohol-enhanced aggressiveness of breast cancer. Cancer stem cells (CSCs) play a critical role in cancer metastasis and recurrence.

Methods

We evaluated the effect of chronic alcohol exposure on mammary tumor development/metastasis in MMTV-neu transgenic mice and investigated the cell signaling in response to alcohol exposure in breast cancer cells overexpressing ErbB2/HER2.

Results and discussion

Chronic alcohol exposure increased breast cancer stem cell-like CSC population and enhanced the lung and colon metastasis in MMTV-neu transgenic mice. Alcohol exposure caused a drastic increase in CSC population and mammosphere formation in breast cancer cells overexpressing ErbB2/HER2. Alcohol exposure stimulated the phosphorylation of p38γ MAPK (p-p38γ) which was co-localized with phosphorylated ErbB2 and CSCs in the mammary tumor tissues. In vitro results confirmed that alcohol activated ErbB2/HER2 and selectively increased p-p38γ MAPK as well as the interaction between p38γ MAPK and its substrate, SAP97. However, alcohol did not affect the expression/phosphorylation of p38α/β MAPKs. In breast cancer cell lines, high expression of ErbB2 and p-p38γ MAPK was generally correlated with more CSC population. Blocking ErbB2 signaling abolished heregulin β1- and alcohol-stimulated p-p38γ MAPK and its association with SAP97. More importantly, p38γ MAPK siRNA significantly inhibited an alcohol-induced increase in CSC population, mammosphere formation and migration/invasion of breast cancer cells overexpressing ErbB2.

Conclusions

p38γ MAPK is downstream of ErbB2 and plays an important role in alcohol-enhanced aggressiveness of breast cancer. Therefore, in addition to ErbB2/HER2, p38γ MAPK may be a potential target for the treatment of alcohol-enhanced cancer aggressiveness.
Appendix
Available only for authorised users
Literature
1.
Group UCSW. United States Cancer Statistics: 1999-2011 incidence and mortality web-based report. Atlanta (GA): Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute; 2014.
2.
Roswall N, Weiderpass E. Alcohol as a Risk Factor for Cancer: Existing Evidence in a Global Perspective. J Preventive Med Public Health. 2015;48:1.
3.
Scoccianti C, Lauby-Secretan B, Bello PY, Chajes V, Romieu I. Female breast cancer and alcohol consumption: a review of the literature. Am J Prev Med. 2014;46:S16–25.CrossRefPubMed
4.
McDonald JA, Goyal A, Terry MB. Alcohol intake and breast cancer risk: weighing the overall evidence. Curr Breast Cancer Reports. 2013;5:208–21.CrossRef
5.
Stoll BA. Alcohol intake and late-stage promotion of breast cancer. Eur J Cancer. 1999;35:1653–8.CrossRefPubMed
6.
Vaeth PA, Satariano WA. Alcohol consumption and breast cancer stage at diagnosis. Alcohol Clin Exp Res. 1998;22:928–34.CrossRefPubMed
7.
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. Br J Cancer. 1996;73:1298.CrossRefPubMedPubMedCentral
8.
Aye MM, Ma C, Lin H, Bower KA, Wiggins RC, Luo J. Ethanol-induced in vitro invasion of breast cancer cells: the contribution of MMP-2 by fibroblasts. Int J Cancer. 2004;112:738–46.CrossRefPubMed
9.
Fan S, Meng Q, Gao B, Grossman J, Yadegari M, Goldberg ID, Rosen EM. Alcohol stimulates estrogen receptor signaling in human breast cancer cell lines. Cancer Res. 2000;60:5635–9.PubMed
10.
Forsyth CB, Tang Y, Shaikh M, Zhang L, Keshavarzian A. Alcohol stimulates activation of Snail, epidermal growth factor receptor signaling, and biomarkers of epithelialGÇômesenchymal transition in colon and breast cancer cells. Alcohol Clin Exp Res. 2010;34:19–31.CrossRefPubMed
11.
Izevbigie EB, Ekunwe SI, Jordan J, Howard CB. Ethanol modulates the growth of human breast cancer cells in vitro. Exp Biol Med (Maywood). 2002;227:260–5.
12.
Ke Z, Lin H, Fan Z, Cai TQ, Kaplan RA, Ma C, Bower KA, Shi X, Luo J. MMP-2 mediates ethanol-induced invasion of mammary epithelial cells over-expressing ErbB2. Int J Cancer. 2006;119:8–16.CrossRefPubMed
13.
Luo J. Role of matrix metalloproteinase-2 in ethanol-induced invasion by breast cancer cells. J Gastroenterol Hepatol. 2006;21 Suppl 3:S65–8.CrossRefPubMed
14.
Luo J, Miller MW. Ethanol enhances erbB-mediated migration of human breast cancer cells in culture. Breast Cancer Res Treat. 2000;63:61–9.CrossRefPubMed
15.
Ma C, Lin H, Leonard SS, Shi X, Ye J, Luo J. Overexpression of ErbB2 enhances ethanol-stimulated intracellular signaling and invasion of human mammary epithelial and breast cancer cells in vitro. Oncogene. 2003;22:5281–90.CrossRefPubMed
16.
Meng Q, Gao B, Goldberg ID, Rosen EM, Fan S. Stimulation of cell invasion and migration by alcohol in breast cancer cells. Biochem Biophys Res Commun. 2000;273:448–53.CrossRefPubMed
17.
Singletary K. Ethanol and experimental breast cancer: a review. Alcohol Clin Exp Res. 1997;21:334–9.PubMed
18.
Wang S, Xu M, Li F, Wang X, Bower KA, Frank JA, Lu Y, Chen G, Zhang Z, Ke Z, et al. Ethanol promotes mammary tumor growth and angiogenesis: the involvement of chemoattractant factor MCP-1. Breast Cancer Res Treat. 2012;133:1037–48.CrossRefPubMed
19.
Watabiki T, Okii Y, Tokiyasu T, Yoshimura S, Yoshida M, Akane A, Shikata N, Tsubura A. Long-term ethanol consumption in ICR mice causes mammary tumor in females and liver fibrosis in males. Alcohol Clin Exp Res. 2000;24:117S–22S.PubMed
20.
Wong AW, Paulson QX, Hong J, Stubbins RE, Poh K, Schrader E, Nunez NP. Alcohol promotes breast cancer cell invasion by regulating the Nm23-ITGA5 pathway. J Exp Clin Cancer Res. 2011;30:75.CrossRefPubMedPubMedCentral
21.
Xu M, Bower KA, Wang S, Frank JA, Chen G, Ding M, Wang S, Shi X, Ke Z, Luo J. Cyanidin-3-glucoside inhibits ethanol-induced invasion of breast cancer cells overexpressing ErbB2. Mol Cancer. 2010;9:285.CrossRefPubMedPubMedCentral
22.
Xu M, Bower KA, Chen G, Shi X, Dong Z, Ke Z, Luo J. Ethanol enhances the interaction of breast cancer cells over-expressing ErbB2 with fibronectin. Alcohol Clin Exp Res. 2010;34:751–60.CrossRefPubMed
23.
Paterson MC, Dietrich KD, Danyluk J, Paterson AH, Lees AW, Jamil N, Hanson J, Jenkins H, Krause BE, McBlain WA. Correlation between c-erbB-2 amplification and risk of recurrent disease in node-negative breast cancer. Cancer Res. 1991;51:556–67.PubMed
24.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.CrossRefPubMed
25.
Ali HR, Dawson SJ, Blows FM, Provenzano E, Pharoah PD, Caldas C. Cancer stem cell markers in breast cancer: pathological, clinical and prognostic significance. Breast Cancer Res. 2011;13:R118.CrossRefPubMedPubMedCentral
26.
Charafe-Jauffret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P, Hur MH, Diebel ME, Monville F, Dutcher J, et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res. 2009;69:1302–13.CrossRefPubMedPubMedCentral
27.
Korkaya H, Paulson A, Iovino F, Wicha MS. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene. 2008;27:6120–30.CrossRefPubMedPubMedCentral
28.
Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochimica et Biophysica Acta (BBA)-Mole Cell Res. 2007;1773:1358–75.CrossRef
29.
Rosenthal DT, Iyer H, Escudero S, Bao L, Wu Z, Ventura AC, Kleer CG, Arruda EM, Garikipati K, Merajver SD. p38 + ¦ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior. Cancer Res. 2011;71:6338–49.CrossRefPubMedPubMedCentral
30.
Luo J, West JR, Cook RT, Pantazis NJ. Ethanol induces cell death and cell cycle delay in cultures of pheochromocytoma PC12 cells. Alcohol Clin Exp Res. 1999;23:644–56.CrossRefPubMed
31.
Luo J, Miller MW. 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. 1997;21:1186–94.PubMed
32.
Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ. Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem. 1995;270:7420–6.CrossRefPubMed
33.
Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555–67.CrossRefPubMedPubMedCentral
34.
Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, Wicha MS. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 2003;17:1253–70.CrossRefPubMedPubMedCentral
35.
Dontu G, Wicha MS. Survival of mammary stem cells in suspension culture: implications for stem cell biology and neoplasia. J Mammary Gland Biol Neoplasia. 2005;10:75–86.CrossRefPubMed
36.
Ji Z, Fan Z, Zhang Y, Yu R, Yang H, Zhou C, Luo J, Ke ZJ. Thiamine deficiency promotes T cell infiltration in experimental autoimmune encephalomyelitis: the involvement of CCL2. J Immunol. 2014;193:2157–67.CrossRefPubMedPubMedCentral
37.
Kuma Y, Sabio G, Bain J, Shpiro N, Marquez R, Cuenda A. BIRB796 inhibits all p38 MAPK isoforms in vitro and in vivo. J Biol Chem. 2005;280:19472–9.CrossRefPubMed
38.
Sabio G, Arthur JS, Kuma Y, Peggie M, Carr J, Murray-Tait V, Centeno F, Goedert M, Morrice NA, Cuenda A. p38gamma regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP. EMBO J. 2005;24:1134–45.CrossRefPubMedPubMedCentral
39.
40.
Ricardo S, Vieira AF, Gerhard R, Leitão D, Pinto R, Cameselle-Teijeiro JF, Milanezi F, Schmitt F, Paredes J: Breast cancer stem cell markers CD44, CD24 and ALDH1: expression distribution within intrinsic molecular subtype. J Clin Pathol 2011;64:937–46.CrossRefPubMed
41.
de Beça FF, Caetano P, Gerhard R, Alvarenga CA, Gomes M, Paredes J, Schmitt F. Cancer stem cells markers CD44, CD24 and ALDH1 in breast cancer special histological types. J Clin Pathol. 2013;66:187–91.CrossRefPubMed
42.
Meng F, Zhang H, Liu G, Kreike B, Chen W, Sethi S, Miller FR, Wu G. p38 + ¦ mitogen-activated protein kinase contributes to oncogenic properties maintenance and resistance to poly (ADP-ribose)-polymerase-1 inhibition in breast cancer. Neoplasia. 2011;13:472–IN425.CrossRefPubMedPubMedCentral
43.
Caruana G, Bernstein A. Craniofacial dysmorphogenesis including cleft palate in mice with an insertional mutation in the discs large gene. Mol Cell Biol. 2001;21:1475–83.CrossRefPubMedPubMedCentral
44.
Mendoza-Topaz C, Urra F, Barria R, Albornoz V, Ugalde D, Thomas U, Gundelfinger ED, Delgado R, Kukuljan M, Sanxaridis PD, et al. DLGS97/SAP97 is developmentally upregulated and is required for complex adult behaviors and synapse morphology and function. J Neurosci. 2008;28:304–14.CrossRefPubMedPubMedCentral
45.
46.
Etienne-Manneville S, Manneville J-B, Nicholls S, Ferenczi MA, Hall A. Cdc42 and Par6–PKCζ regulate the spatially localized association of Dlg1 and APC to control cell polarization. J Cell Biol. 2005;170:895–901.CrossRefPubMedPubMedCentral
47.
O’Neill AK, Gallegos LL, Justilien V, Garcia EL, Leitges M, Fields A, Hall RA, Newton AC. PKCα interacts with its novel substrate discs large homolog (DLG) 1 to promote cellular migration. J Biol Chem. 2011;286:43559–68.CrossRefPubMedPubMedCentral
48.
Sturchler E, Feurstein D, McDonald P, Duckett D. Mechanism of oxidative stress-induced ASK1-catalyzed MKK6 phosphorylation. Biochemistry. 2010;49:4094–102.CrossRefPubMed
Metadata
Title
ErbB2 and p38γ MAPK mediate alcohol-induced increase in breast cancer stem cells and metastasis
Authors
Mei Xu
Zhenhua Ren
Xin Wang
Ashley Comer
Jacqueline A. Frank
Zun-ji Ke
Yi Huang
Zhuo Zhang
Xianglin Shi
Siying Wang
Jia Luo
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2016
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-016-0532-4

Other articles of this Issue 1/2016

Molecular Cancer 1/2016 Go to the issue

Review

Synthetic lethality in lung cancer and translation to clinical therapies

Research

Deregulated expression of cryptochrome genes in human colorectal cancer

Research

Combination of the novel histone deacetylase inhibitor YCW1 and radiation induces autophagic cell death through the downregulation of BNIP3 in triple-negative breast cancer cells in vitro and in an orthotopic mouse model

Research

Higher levels of TIMP-1 expression are associated with a poor prognosis in triple-negative breast cancer

Research

Rad51C-ATXN7 fusion gene expression in colorectal tumors

Research

Mutation of epigenetic regulators TET2 and MLL3 in patients with HTLV-I-induced acute adult T-cell leukemia
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits