DMBA promotes ErbB2‑mediated carcinogenesis via ErbB2 and estrogen receptor pathway activation and genomic instability

  • Authors:
    • Zhikun Ma
    • Young Mi Kim
    • Erin W. Howard
    • Xiaoshan Feng
    • Stanley D. Kosanke
    • Shihe Yang
    • Yunbo Jiang
    • Amanda B. Parris
    • Xia Cao
    • Shibo Li
    • Xiaohe Yang
  • View Affiliations

  • Published online on: July 4, 2018     https://doi.org/10.3892/or.2018.6545
  • Pages: 1632-1640
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Abstract

Environmental factors, including 7,12‑dimethylbenz[a]anthracene (DMBA) exposure, and genetic predisposition, including ErbB2 overexpression/amplification, have been demonstrated to increase breast cancer susceptibility. Although DMBA‑ and ErbB2‑mediated breast cancers are well‑studied in their respective models, key interactions between environmental and genetic factors on breast cancer risk remain unclear. Therefore, the present study aimed to investigate the effect of DMBA exposure on ErbB2‑mediated mammary tumorigenesis. MMTV‑ErbB2 transgenic mice exposed to DMBA (1 mg) via weekly oral gavage for 6 weeks exhibited significantly enhanced mammary tumor development, as indicated by reduced tumor latency and increased tumor multiplicity compared with control mice. Whole mount analysis of premalignant mammary tissues from 15‑week‑old mice revealed increased ductal elongation and proliferative index in DMBA‑exposed mice. Molecular analyses of premalignant mammary tissues further indicated that DMBA exposure enhanced epidermal growth factor receptor (EGFR)/ErbB2 and estrogen receptor (ER) signaling, which was associated with increased mRNA levels of EGFR/ErbB2 family members and ER‑targeted genes. Furthermore, analysis of tumor karyotypes revealed that DMBA‑exposed tumors displayed more chromosomal alterations compared with control tumors, implicating DMBA‑induced chromosomal instability in tumor promotion in this model. Together, the data suggested that DMBA‑induced deregulation of EGFR/ErbB2‑ER pathways plays a critical role in the enhanced chromosomal instability and promotion of ErbB2‑mediated mammary tumorigenesis. The study highlighted gene‑environment interactions that may increase risk of breast cancer, which is a critical clinical issue.

References

1 

Nowell SA, Ahn J and Ambrosone CB: Gene-nutrient interactions in cancer etiology. Nutr Rev. 62:427–438. 2004. View Article : Google Scholar : PubMed/NCBI

2 

Song M, Lee KM and Kang D: Breast cancer prevention based on gene-environment interaction. Mol Carcinog. 50:280–290. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Chia KS: Gene-environment interactions in breast cancer. Novartis Found Symp. 293:143–150; discussion 150–155, 181–183. 2008. View Article : Google Scholar : PubMed/NCBI

4 

Rubin BS: Bisphenol A: An endocrine disruptor with widespread exposure and multiple effects. J Steroid Biochem Mol Biol. 127:27–34. 2011. View Article : Google Scholar : PubMed/NCBI

5 

Belpomme D, Irigaray P, Hardell L, Clapp R, Montagnier L, Epstein S and Sasco AJ: The multitude and diversity of environmental carcinogens. Environ Res. 105:414–429. 2007. View Article : Google Scholar : PubMed/NCBI

6 

Schell LM, Burnitz KK and Lathrop PW: Pollution and human biology. Ann Hum Biol. 37:347–366. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Majkova Z, Toborek M and Hennig B: The role of caveolae in endothelial cell dysfunction with a focus on nutrition and environmental toxicants. J Cell Mol Med. 14:2359–2370. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Rybicki BA, Nock NL, Savera AT, Tang D and Rundle A: Polycyclic aromatic hydrocarbon-DNA adduct formation in prostate carcinogenesis. Cancer Lett. 239:157–167. 2006. View Article : Google Scholar : PubMed/NCBI

9 

Singhal R, Shankar K, Badger TM and Ronis MJ: Estrogenic status modulates aryl hydrocarbon receptor-mediated hepatic gene expression and carcinogenicity. Carcinogenesis. 29:227–236. 2008. View Article : Google Scholar : PubMed/NCBI

10 

Mehta RG, Naithani R, Huma L, Hawthorne M, Moriarty RM, McCormick DL, Steele VE and Kopelovich L: Efficacy of chemopreventive agents in mouse mammary gland organ culture (MMOC) model: A comprehensive review. Curr Med Chem. 15:2785–2825. 2008. View Article : Google Scholar : PubMed/NCBI

11 

Currier N, Solomon SE, Demicco EG, Chang DL, Farago M, Ying H, Dominguez I, Sonenshein GE, Cardiff RD, Xiao ZX, et al: Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors. Toxicol Pathol. 33:726–737. 2005. View Article : Google Scholar : PubMed/NCBI

12 

Nebert DW, Petersen DD and Fornace AJ Jr: Cellular responses to oxidative stress: The [Ah] gene battery as a paradigm. Environ Health Perspect. 88:13–25. 1990. View Article : Google Scholar : PubMed/NCBI

13 

Rundle A, Tang D, Hibshoosh H, Estabrook A, Schnabel F, Cao W, Grumet S and Perera FP: The relationship between genetic damage from polycyclic aromatic hydrocarbons in breast tissue and breast cancer. Carcinogenesis. 21:1281–1289. 2000. View Article : Google Scholar : PubMed/NCBI

14 

Papaconstantinou AD, Shanmugam I, Shan L, Schroeder IS, Qiu C, Yu M and Snyderwine EG: Gene expression profiling in the mammary gland of rats treated with 7,12-dimethylbenz[a]anthracene. Int J Cancer. 118:17–24. 2006. View Article : Google Scholar : PubMed/NCBI

15 

Liu E, Thor A, He M, Barcos M, Ljung BM and Benz C: The HER2 (c-erbB-2) oncogene is frequently amplified in in situ carcinomas of the breast. Oncogene. 7:1027–1032. 1992.PubMed/NCBI

16 

Jardines L, Weiss M and Fowble B: Greene Mneu(c-erbB-2/HER2) and the epidermal growth factor receptor (EGFR) in breast cancer. Pathobiology. 61:268–282. 1993. View Article : Google Scholar : PubMed/NCBI

17 

Hynes NE and Stern DF: The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta. 1198:165–184. 1994.PubMed/NCBI

18 

Citri A and Yarden Y: EGF-ERBB signalling: Towards the systems level. Nat Rev Mol Cell Biol. 7:505–516. 2006. View Article : Google Scholar : PubMed/NCBI

19 

Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD and 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. View Article : Google Scholar : PubMed/NCBI

20 

Bouchard L, Lamarre L, Tremblay PJ and Jolicoeur P: Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene. Cell. 57:931–936. 1989. View Article : Google Scholar : PubMed/NCBI

21 

Marcotte R and Muller WJ: Signal transduction in transgenic mouse models of human breast cancer-implications for human breast cancer. J Mammary Gland Biol Neoplasia. 13:323–335. 2008. View Article : Google Scholar : PubMed/NCBI

22 

Hutchinson JN and Muller WJ: Transgenic mouse models of human breast cancer. Oncogene. 19:6130–6137. 2000. View Article : Google Scholar : PubMed/NCBI

23 

Yang X, Yang S, McKimmey C, Liu B, Edgerton SM, Bales W, Archer LT and Thor AD: Genistein induces enhanced growth promotion in ER-positive/erbB-2-overexpressing breast cancers by ER-erbB-2 cross talk and p27/kip1 downregulation. Carcinogenesis. 31:695–702. 2010. View Article : Google Scholar : PubMed/NCBI

24 

Yang X, Edgerton SM, Kosanke SD, Mason TL, Alvarez KM, Liu N, Chatterton RT, Liu B, Wang Q, Kim A, et al: Hormonal and dietary modulation of mammary carcinogenesis in mouse mammary tumor virus-c-erbB-2 transgenic mice. Cancer Res. 63:2425–2433. 2003.PubMed/NCBI

25 

Warin R, Chambers WH, Potter DM and Singh SV: Prevention of mammary carcinogenesis in MMTV-neu mice by cruciferous vegetable constituent benzyl isothiocyanate. Cancer Res. 69:9473–9480. 2009. View Article : Google Scholar : PubMed/NCBI

26 

Shen K and Novak RF: DDT stimulates c-erbB2, c-met, and STATS tyrosine phosphorylation, Grb2-Sos association, MAPK phosphorylation, and proliferation of human breast epithelial cells. Biochem Biophys Res Commun. 231:17–21. 1997. View Article : Google Scholar : PubMed/NCBI

27 

Shan L, Yu M and Snyderwine EG: Global gene expression profiling of chemically induced rat mammary gland carcinomas and adenomas. Toxicol Pathol. 33:768–775. 2005. View Article : Google Scholar : PubMed/NCBI

28 

Shan L, He M, Yu M, Qiu C, Lee NH, Liu ET and Snyderwine EG: cDNA microarray profiling of rat mammary gland carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 7,12-dimethylbenz[a]anthracene. Carcinogenesis. 23:1561–1568. 2002. View Article : Google Scholar : PubMed/NCBI

29 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

30 

Kim YM, Ma Z, Lee S, Lee J, Li S and Yang X: Trisomy chromosome 5 is a recurrent cytogenetic lesion in mammary tumors from parous MMTV-erbB-2 transgenic mice. Oncol Lett. 2:1077–1081. 2011. View Article : Google Scholar : PubMed/NCBI

31 

de Oliveira Andrade F, Fontelles CC, Rosim MP, de Oliveira TF, de Melo Loureiro AP, Mancini-Filho J, Rogero MM, Moreno FS, de Assis S, Barbisan LF, et al: Exposure to lard-based high-fat diet during fetal and lactation periods modifies breast cancer susceptibility in adulthood in rats. J Nutr Biochem. 25:613–622. 2014. View Article : Google Scholar : PubMed/NCBI

32 

Qin LQ, Xu JY, Tezuka H, Wang PY and Hoshi K: Commercial soy milk enhances the development of 7,12-dimethylbenz(a) anthracene-induced mammary tumors in rats. In Vivo. 21:667–671. 2007.PubMed/NCBI

33 

Qi C, Lan H, Ye J, Li W, Wei P, Yang Y, Guo S, Lan T, Li J, Zhang Q, et al: Slit2 promotes tumor growth and invasion in chemically induced skin carcinogenesis. Lab Invest. 94:766–776. 2014. View Article : Google Scholar : PubMed/NCBI

34 

Muller WJ, Sinn E, Pattengale PK, Wallace R and Leder P: Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell. 54:105–115. 1988. View Article : Google Scholar : PubMed/NCBI

35 

Mohibi S, Mirza S, Band H and Band V: Mouse models of estrogen receptor-positive breast cancer. J Carcinog. 10:352011. View Article : Google Scholar : PubMed/NCBI

36 

Cool M, Depault F and Jolicoeur P: Fine allelotyping of Erbb2-induced mammary tumors in mice reveals multiple discontinuous candidate regions of tumor-suppressor loci. Genes Chromosomes Cancer. 45:191–202. 2006. View Article : Google Scholar : PubMed/NCBI

37 

Liu S, Liu W, Jakubczak JL, Erexson GL, Tindall KR, Chan R, Muller WJ, Adhya S, Garges S and Merlino G: Genetic instability favoring transversions associated with ErbB2-induced mammary tumorigenesis. Proc Natl Acad Sci USA. 99:3770–3775. 2002. View Article : Google Scholar : PubMed/NCBI

38 

Daniel FB and Joyce NJ: DNA adduct formation by 7, 12-dimethylbenz[a]anthracene and its noncarcinogenic 2-fluoro analogue in female Sprague-Dawley rats. J Natl Cancer Inst. 70:111–118. 1983.PubMed/NCBI

39 

Russo IH and Russo J: Mammary gland neoplasia in long-term rodent studies. Environ Health Perspect. 104:938–967. 1996. View Article : Google Scholar : PubMed/NCBI

40 

Umekita Y, Souda M, Hatanaka K, Hamada T, Yoshioka T, Kawaguchi H and Tanimoto A: Gene expression profile of terminal end buds in rat mammary glands exposed to diethylstilbestrol in neonatal period. Toxicol Lett. 205:15–25. 2011. View Article : Google Scholar : PubMed/NCBI

41 

Hsu PY, Deatherage DE, Rodriguez BA, Liyanarachchi S, Weng YI, Zuo T, Liu J, Cheng AS and Huang TH: Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells. Cancer Res. 69:5936–5945. 2009. View Article : Google Scholar : PubMed/NCBI

42 

Lamartiniere CA, Jenkins S, Betancourt AM, Wang J and Russo J: Exposure to the endocrine disruptor bisphenol a alters susceptibility for mammary cancer. Horm Mol Biol Clin Investig. 5:45–52. 2011.PubMed/NCBI

43 

Wogan GN, Hecht SS, Felton JS, Conney AH and Loeb LA: Environmental and chemical carcinogenesis. Semin Cancer Biol. 14:473–486. 2004. View Article : Google Scholar : PubMed/NCBI

44 

Medina D: Chemical carcinogenesis of rat and mouse mammary glands. Breast Dis. 28:63–68. 2007. View Article : Google Scholar : PubMed/NCBI

45 

Plante I, Stewart MK, Barr K, Allan AL and Laird DW: Cx43 suppresses mammary tumor metastasis to the lung in a Cx43 mutant mouse model of human disease. Oncogene. 30:1681–1692. 2011. View Article : Google Scholar : PubMed/NCBI

46 

Russo J and Russo IH: Influence of differentiation and cell kinetics on the susceptibility of the rat mammary gland to carcinogenesis. Cancer Res. 40:2677–2687. 1980.PubMed/NCBI

47 

Markey CM, Luque EH, Munoz De Toro M, Sonnenschein C and Soto AM: In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland. Biol Reprod. 65:1215–1223. 2001. View Article : Google Scholar : PubMed/NCBI

48 

Coffey RJ Jr, Meise KS, Matsui Y, Hogan BL, Dempsey PJ and Halter SA: Acceleration of mammary neoplasia in transforming growth factor alpha transgenic mice by 7,12-dimethylbenzanthracene. Cancer Res. 54:1678–1683. 1994.PubMed/NCBI

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APA
Ma, Z., Kim, Y.M., Howard, E.W., Feng, X., Kosanke, S.D., Yang, S. ... Yang, X. (2018). DMBA promotes ErbB2‑mediated carcinogenesis via ErbB2 and estrogen receptor pathway activation and genomic instability. Oncology Reports, 40, 1632-1640. https://doi.org/10.3892/or.2018.6545
MLA
Ma, Z., Kim, Y. M., Howard, E. W., Feng, X., Kosanke, S. D., Yang, S., Jiang, Y., Parris, A. B., Cao, X., Li, S., Yang, X."DMBA promotes ErbB2‑mediated carcinogenesis via ErbB2 and estrogen receptor pathway activation and genomic instability". Oncology Reports 40.3 (2018): 1632-1640.
Chicago
Ma, Z., Kim, Y. M., Howard, E. W., Feng, X., Kosanke, S. D., Yang, S., Jiang, Y., Parris, A. B., Cao, X., Li, S., Yang, X."DMBA promotes ErbB2‑mediated carcinogenesis via ErbB2 and estrogen receptor pathway activation and genomic instability". Oncology Reports 40, no. 3 (2018): 1632-1640. https://doi.org/10.3892/or.2018.6545