Markers of epithelial-mesenchymal transition in an experimental breast cancer model induced by organophosphorous pesticides and estrogen (Review)

Calaf,Gloria M.; Bleak,Tammy C.; Muñoz,Juan P.; Aguayo,Francisco

doi:10.3892/ol.2020.11945

Markers of epithelial-mesenchymal transition in an experimental breast cancer model induced by organophosphorous pesticides and estrogen (Review)

Authors:
- Gloria M. Calaf
- Tammy C. Bleak
- Juan P. Muñoz
- Francisco Aguayo
View Affiliations

Affiliations: Instituto de Alta Investigación, Universidad de Tarapacá, Arica 1000000, Chile, Programa de Virología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380000, Chile
Published online on: August 5, 2020 https://doi.org/10.3892/ol.2020.11945
Article Number: 84
Copyright: © Calaf et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Breast cancer is a major health problem and accounted for 11.6% of all new cancer cases and 6.6% of all cancer deaths among women worldwide in 2018. However, its etiology has remained elusive. According to epidemiological studies, environmental factors are influencing the increase in the incidence of breast cancer risk. Components such as chemicals, including pesticides, are agents that produce deleterious effects on wildlife and humans. Among them, the organophosphorus pesticides, such as malathion, have largely been considered in this etiology. The epithelial‑mesenchymal transition serves a key role in tumor progression and it is proposed that malathion is closely associated with the origin of this transition, among other causes. Moreover, proteins participating in this process are primordial in the transformation of a normal cell to a malignant tumor cell. The aim of the current study was to evaluate markers that indicated oncogenic properties. The results indicated greater expression levels of proteins associated with the epithelial‑to‑mesenchymal transition, including E‑cadherin, Vimentin, Axl, and Slug in the rat mammary glands treated with malathion alone and combined with estrogen. Atropine was demonstrated to counteract the malathion effect as a muscarinic antagonist. The understanding of the use of markers in experimental models is crucial to identify different stages in the cancer process. The alteration of these markers may serve as a predicting factor that can be used to indicate whether a person has altered ducts or lobules in breast tissue within biopsies of individuals exposed to OPs or other environmental substances.

View Figures

View References

1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Knower KC, To SQ, Leung YK, Ho SM and Clyne CD: Endocrine disruption of the epigenome: A breast cancer link. Endocr Relat Cancer. 21:T33–T55. 2014. View Article : Google Scholar : PubMed/NCBI
3	Grube A, Donaldson D, Kiely T and Wu L: Pesticide industry sales and usage: 2006 and 2007 market estimates. US Environmental Protection Agency. (Washington DC). 2011.Aug. 2018
4	EPA, . Mosquito control: Malathion. US Environmental Protection Agency. 2014.Aug. 2018
5	IARC, . Agents classified by the IARC monographs. 1-122:International Agency for Research on Cancer, World Health Organization. (Lyon, France). 2018.Aug. 2018
6	De Roos AJ, Zahm SH, Cantor KP, Weisenburger DD, Holmes FF, Burmeister LF and Blair A: Integrative assessment of multiple pesticides as risk factors for non-Hodgkin's lymphoma among men. Occup Environ Med. 60:E112003. View Article : Google Scholar : PubMed/NCBI
7	McDuffie HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, Robson D, Skinnider LF and Choi NW: Non-Hodgkin's lymphoma and specific pesticide exposures in men: Cross-canada study of pesticides and health. Cancer Epidemiol Biomarkers Prev. 10:1155–1163. 2001.PubMed/NCBI
8	Mills PK and Yang R: Prostate cancer risk in California farm workers. J Occup Environ Med. 45:249–258. 2003. View Article : Google Scholar : PubMed/NCBI
9	Pesatori AC, Sontag JM, Lubin JH, Consonni D and Blair A: Cohort mortality and nested case-control study of lung cancer among structural pest control workers in Florida (United States). Cancer Causes Control. 5:310–318. 1994. View Article : Google Scholar : PubMed/NCBI
10	Miligi L, Costantini AS, Bolejack V, Veraldi A, Benvenuti A, Nanni O, Ramazzotti V, Tumino R, Stagnaro E, Rodella S, et al: Non-Hodgkin's lymphoma, leukemia, and exposures in agriculture: Results from the Italian multicenter case-control study. Am J Ind Med. 44:627–636. 2003. View Article : Google Scholar : PubMed/NCBI
11	Klaasen C: Nonmetallic environmental toxicants: Air pollutants, solvents and vapors, and pesticides. In: The Pharmacological Basis of Therapeutics. Goodman RT, Gilman A, Nies AS and Taylor P: Pergamon Press Inc; New York: pp. 1615–1635. 1990
12	EPA, . Registration review; Draft malathion human health risk assessment. US Environmental Protection Agency. (Washington DC). 2016.Aug. 2018
13	EPA, . Revised Chlorpyrifos Human Health Risk Assessment. US Environmental Protection Agency. (Washington DC). 2014.http://www.regulations.gov/Aug. 2018
14	Bernieri T, Moraes MF, Ardenghi PG and Basso da Silva L: Assessment of DNA damage and cholinesterase activity in soybean farmers in southern Brazil: High versus low pesticide exposure. J Environ Sci Health B. 55:355–360. 2020. View Article : Google Scholar : PubMed/NCBI
15	Kapka-Skrzypczak L, Cyranka M, Skrzypczak M and Kruszewski M: Biomonitoring and biomarkers of organophosphate pesticides exposure-state of the art. Ann Agric Environ Med. 18:294–303. 2011.PubMed/NCBI
16	Shah HK, Sharma T and Banerjee BD: Organochlorine pesticides induce inflammation, ROS production, and DNA damage in human epithelial ovary cells: An in vitro study. Chemosphere. 246:1256912020. View Article : Google Scholar : PubMed/NCBI
17	Guyton KZ, Loomis D, Grosse Y, El Ghissassi F, Benbrahim-Tallaa L, Guha N, Scoccianti C, Mattock H and Straif K; International Agency for Research on Cancer Monograph Working Group, IARC, Lyon, France, : Carcinogenicity of tetrachlorvinphos, parathion, malathion, diazinon, and glyphosate. Lancet Oncol. 16:490–491. 2015. View Article : Google Scholar : PubMed/NCBI
18	IARC, . Some organophosphate insecticides and herbicides. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. 112:International Agency for Research on Cancer. (Lyon, France). 2017.https://monographs.iarc.fr/iarc-monographs-on-the-evaluation-of-carcinogenic-risks-to-humans-4/July. 2017
19	Elobeid MA, Padilla MA, Brock DW, Ruden DM and Allison DB: Endocrine disruptors and obesity: An examination of selected persistent organic pollutants in the NHANES 1999–2002 data. Int J Environ Res Public Health. 7:2988–3005. 2010. View Article : Google Scholar : PubMed/NCBI
20	Everett CJ, Frithsen IL, Diaz VA, Koopman RJ, Simpson WM Jr and Mainous AG III: Association of a polychlorinated dibenzo-p-dioxin, a polychlorinated biphenyl, and DDT with diabetes in the 1999–2002 national health and nutrition examination Survey. Environ Res. 103:413–418. 2007. View Article : Google Scholar : PubMed/NCBI
21	Beard J; Australian Rural Health Research Collaboration, : DDT and human health. Sci Total Environ. 355:78–89. 2006. View Article : Google Scholar : PubMed/NCBI
22	Calaf GM, Parra E and Garrido F: Cell proliferation and tumor formation induced by eserine, an acetylcholinesterase inhibitor, in rat mammary gland. Oncol Rep. 17:25–33. 2007.PubMed/NCBI
23	Calaf GM and Garrido F: Catechol estrogens as biomarkers for mammary gland cancer. Int J Oncol. 39:177–183. 2011.PubMed/NCBI
24	Calaf GM and Echiburu-Chau C: Synergistic effect of malathion and estrogen on mammary gland carcinogenesis. Oncol Rep. 28:640–646. 2012. View Article : Google Scholar : PubMed/NCBI
25	Echiburu-Chau C and Calaf GM: Rat lung cancer induced by malathion and estrogen. Int J Oncol. 33:603–611. 2008.PubMed/NCBI
26	Alfaro-Lira S, Pizarro-Ortiz M and Calaf GM: Malignant transformation of rat kidney induced by environmental substances and estrogen. Int J Environ Res Public Health. 9:1630–1648. 2012. View Article : Google Scholar : PubMed/NCBI
27	Calaf GM and Roy D: Human drug metabolism genes in parathion-and estrogen-treated breast cells. Int J Mol Med. 20:875–881. 2007.PubMed/NCBI
28	Calaf GM and Roy D: Gene and protein expressions induced by 17beta-estradiol and parathion in cultured breast epithelial cells. Mol Med. 13:255–265. 2007. View Article : Google Scholar : PubMed/NCBI
29	Calaf GM and Roy D: Gene expression signature of parathion-transformed human breast epithelial cells. Int J Mol Med. 19:741–750. 2007.PubMed/NCBI
30	Calaf GM and Roy D: Cancer genes induced by malathion and parathion in the presence of estrogen in breast cells. Int J Mol Med. 21:261–268. 2008.PubMed/NCBI
31	Calaf GM and Roy D: Cell adhesion proteins altered by 17beta estradiol and parathion in breast epithelial cells. Oncol Rep. 19:165–169. 2008.PubMed/NCBI
32	Calaf GM, Echiburu-Chau C and Roy D: Organophosphorous pesticides and estrogen induce transformation of breast cells affecting p53 and c-Ha-ras genes. Int J Oncol. 35:1061–1068. 2009. View Article : Google Scholar : PubMed/NCBI
33	Cabello G, Valenzuela M, Vilaxa A, Duran V, Rudolph I, Hrepic N and Calaf G: A rat mammary tumor model induced by the organophosphorous pesticides parathion and malathion, possibly through acetylcholinesterase inhibition. Environ Health Perspect. 109:471–479. 2001. View Article : Google Scholar : PubMed/NCBI
34	Hoon Tan P, Ellis I, Allison K, Brogi E, Fox SB, Lakhani S, Lazar AJ, Morris EA, Sahin A, Salgado R, et al: The 2019 WHO classification of tumours of the breast. Histopathology. Feb 13–2020.(Epub ahead of print). PubMed/NCBI
35	Taylor P: Anticholinesterase agents. In: The Pharmacological Basis of Therapeutics. Goodman RT, Gilman A, Nies AS and Taylor P: Pergamon Press Inc.; New York: pp. 131–147. 1990, PubMed/NCBI
36	Omran OM and Omer OH: The effects of alpha-lipoic acid on breast of female albino rats exposed to malathion: Histopathological and immunohistochemical study. Pathol Res Pract. 211:462–469. 2015. View Article : Google Scholar : PubMed/NCBI
37	Nilsson E, Klukovich R, Sadler-Riggleman I, Beck D, Xie Y, Yan W and Skinner MK: Environmental toxicant induced epigenetic transgenerational inheritance of ovarian pathology and granulosa cell epigenome and transcriptome alterations: Ancestral origins of polycystic ovarian syndrome and primary ovarian insufiency. Epigenetics. 13:875–895. 2018. View Article : Google Scholar : PubMed/NCBI
38	Skinner MK, Manikkam M, Tracey R, Guerrero-Bosagna C, Haque M and Nilsson EE: Ancestral dichlorodiphenyltrichloroethane (DDT) exposure promotes epigenetic transgenerational inheritance of obesity. BMC Med. 11:2282013. View Article : Google Scholar : PubMed/NCBI
39	Kao CC, Que DE, Bongo SJ, Tayo LL, Lin YH, Lin CW, Lin SL, Gou YY, Hsu WL, Shy CG, et al: Residue levels of organochlorine pesticides in breast milk and its associations with cord blood thyroid hormones and the Offspring's neurodevelopment. Int J Environ Res Public Health. 16:14382019. View Article : Google Scholar
40	Chen L, Jian W, Lu L, Zheng L, Yu Z and Zhou D: Elevated expression of E-cadherin in primary breast cancer and its corresponding metastatic lymph node. Int J Clin Exp Med. 8:11752–11758. 2015.PubMed/NCBI
41	Gumbiner BM: Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev Mol Cell Biol. 6:622–634. 2005. View Article : Google Scholar : PubMed/NCBI
42	Tepass U: Genetic analysis of cadherin function in animal morphogenesis. Curr Opin Cell Biol. 11:540–548. 1999. View Article : Google Scholar : PubMed/NCBI
43	Wheelock MJ and Jensen PJ: Regulation of keratinocyte intercellular junction organization and epidermal morphogenesis by E-cadherin. J Cell Biol. 117:415–425. 1992. View Article : Google Scholar : PubMed/NCBI
44	Jeanes A, Gottardi CJ and Yap AS: Cadherins and cancer: How does cadherin dysfunction promote tumor progression? Oncogene. 27:6920–6929. 2008. View Article : Google Scholar : PubMed/NCBI
45	Shapiro L and Weis WI: Structure and biochemistry of cadherins and catenins. Cold Spring Harb Perspect Biol. 1:a0030532009. View Article : Google Scholar : PubMed/NCBI
46	Perez-Moreno M and Fuchs E: Catenins: Keeping cells from getting their signals crossed. Dev Cell. 11:601–612. 2006. View Article : Google Scholar : PubMed/NCBI
47	Alves CC, Carneiro F, Hoefler H and Becker KF: Role of the epithelial-mesenchymal transition regulator Slug in primary human cancers. Front Biosci (Landmark Ed). 14:3035–3050. 2009. View Article : Google Scholar : PubMed/NCBI
48	Kim J, Bae S, An S, Park JK, Kim EM, Hwang SG, Kim WJ and Um HD: Cooperative actions of p21WAF1 and p53 induce Slug protein degradation and suppress cell invasion. EMBO Rep. 15:1062–1068. 2014. View Article : Google Scholar : PubMed/NCBI
49	Chen J, Imanaka N, Chen J and Griffin JD: Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion. Br J Cancer. 102:351–360. 2010. View Article : Google Scholar : PubMed/NCBI
50	Hajra KM, Chen DY and Fearon ER: The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res. 62:1613–1618. 2002.PubMed/NCBI
51	Wong SHM, Fang CM, Chuah LH, Leong CO and Ngai SC: E-cadherin: Its dysregulation in carcinogenesis and clinical implications. Crit Rev Oncol Hematol. 121:11–22. 2018. View Article : Google Scholar : PubMed/NCBI
52	Liu T, Zhang X, Shang M, Zhang Y, Xia B, Niu M, Liu Y and Pang D: Dysregulated expression of Slug, vimentin, and E-cadherin correlates with poor clinical outcome in patients with basal-like breast cancer. J Surg Oncol. 107:188–194. 2013. View Article : Google Scholar : PubMed/NCBI
53	Myong NH: Loss of E-cadherin and acquisition of vimentin in epithelial-mesenchymal transition are noble indicators of uterine cervix cancer progression. Korean J Pathol. 46:341–348. 2012. View Article : Google Scholar : PubMed/NCBI
54	Guarino M, Rubino B and Ballabio G: The role of epithelial-mesenchymal transition in cancer pathology. Pathology. 39:305–318. 2007. View Article : Google Scholar : PubMed/NCBI
55	Foroni C, Broggini M, Generali D and Damia G: Epithelial-mesenchymal transition and breast cancer: Role, molecular mechanisms and clinical impact. Cancer Treat Rev. 38:689–697. 2012. View Article : Google Scholar : PubMed/NCBI
56	Singh A and Settleman J: EMT, cancer stem cells and drug resistance: An emerging axis of evil in the war on cancer. Oncogene. 29:4741–4751. 2010. View Article : Google Scholar : PubMed/NCBI
57	Calaf GM, Balajee AS, Montalvo-Villagra MT, Leon M, Daniela NM, Alvarez RG, Roy D, Narayan G and Abarca-Quinones J: Vimentin and Notch as biomarkers for breast cancer progression. Oncol Lett. 7:721–727. 2014. View Article : Google Scholar : PubMed/NCBI
58	Davidsen KT, Haaland GS, Lie MK, Lorens JB and Engelsen AST: The role of Axl receptor tyrosine kinase in tumor cell plasticity and therapy resistance. Biomarkers of the Tumor Microenvironment: Basic Studies and Practical Applications. Akslen LA and Watnick RS: Springer; Switzerland: pp. 351–376. 2017, View Article : Google Scholar
59	Meyer AS, Miller MA, Gertler FB and Lauffenburger DA: The receptor AXL diversifies EGFR signaling and limits the response to EGFR-targeted inhibitors in triple-negative breast cancer cells. Sci Signal. 6:ra662013. View Article : Google Scholar : PubMed/NCBI
60	Yanagita M, Arai H, Nakano T, Ohashi K, Mizuno K, Fukatsu A, Doi T and Kita T: Gas6 induces mesangial cell proliferation via latent transcription factor STAT3. J Biol Chem. 276:42364–42369. 2001. View Article : Google Scholar : PubMed/NCBI
61	Linger RM, Keating AK, Earp HS and Graham DK: TAM receptor tyrosine kinases: Biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. 100:35–83. 2008. View Article : Google Scholar : PubMed/NCBI
62	Tai KY, Shieh YS, Lee CS, Shiah SG and Wu CW: Axl promotes cell invasion by inducing MMP-9 activity through activation of NF-kappaB and Brg-1. Oncogene. 27:4044–4055. 2008. View Article : Google Scholar : PubMed/NCBI
63	Calaf GM: Carcinogenicity of malathion and estrogen in an experimental rat mammary gland model. Siberian J Oncol. 17:5–13. 2018. View Article : Google Scholar