Evaluation of melatonin treatment in primary culture of canine mammary tumors

Lopes,Juliana Ramos; Maschio,Larissa Bazela; Jardim-Perassi,Bruna Victorasso; Moschetta,Marina Gobbe; Ferreira,Lívia Carvalho; Martins,Gustavo Rodrigues; Gelaleti,Gabriela Bottaro; De Campos Zuccari,Debora Aparecida Pires

doi:10.3892/or.2014.3596

Evaluation of melatonin treatment in primary culture of canine mammary tumors

Authors:
- Juliana Ramos Lopes
- Larissa Bazela Maschio
- Bruna Victorasso Jardim-Perassi
- Marina Gobbe Moschetta
- Lívia Carvalho Ferreira
- Gustavo Rodrigues Martins
- Gabriela Bottaro Gelaleti
- Debora Aparecida Pires De Campos Zuccari
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Affiliations: Post-graduate Program in Genetics, São Paulo State University (UNESP), São José do Rio Preto, SP, Brazil, Laboratory of Molecular Research in Cancer (LIMC), São José do Rio Preto, SP, Brazil
Published online on: November 11, 2014 https://doi.org/10.3892/or.2014.3596
Pages: 311-319

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Abstract

Mammary neoplasias are the most common tumors observed in female dogs. Identification of these tumors is valuable in order to identify beneficial therapeutic agents as alternative treatments for this tumor type. Oral administration of melatonin appears to exert an oncostatic effect on mammary neoplasia and may have a possible mechanism of action through its interaction with estrogen receptors on epithelial cells. Hence, we analyzed the potential therapeutic value of melatonin in tumors that are estrogen-dependent or -independent, and established a relationship of its action with the expression of the melatonin receptors MT1 and MT2. Furthermore, we analyzed the rate of cell proliferation and apoptosis after treatment with melatonin. Cell cultures were performed using 10 canine mammary tumor fragments and were divided into estrogen receptor (ER)-positive and ER-negative tumors. The results showed that both ER-positive and ER-negative tumors had decreased cell viability and proliferation after treatment with melatonin (p<0.05), although treatment was more effective in the ER-positive tumors. Analysis of the relative expression of the MT1 and MT2 genes by quantitative PCR was performed and the data were compared with the expression of ER in 24 canine mammary tumors and the cellular response to melatonin in 10 samples. MT1 was overexpressed in ER-positive tumors (p<0.05), whereas MT2 was not expressed. Furthermore, melatonin treatment in ER-positive tumors showed an efficient oncostatic effect by inhibiting cell viability and proliferation and inducing apoptosis. These results suggest that melatonin decreased neoplastic mammary cell proliferation and viability and induced apoptosis, with greater efficacy in ER-positive tumors that have a high expression of melatonin receptor MT1. This is a strong evidence for the use of melatonin as a therapeutic agent for estrogen-dependent canine mammary tumors.

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1	Manuali E, De Giuseppe A, Feliziani F, et al: CA 15-3 cell lines and tissue expression in canine mammary cancer and the correlation between serum levels and tumour histological grade. BMC Vet Res. 8:862012. View Article : Google Scholar : PubMed/NCBI
2	Schneider R: Comparison of age, sex, and incidence rates in human and canine breast cancer. Cancer. 26:419–426. 1970. View Article : Google Scholar : PubMed/NCBI
3	Mottolese M, Morelli L, Agrimi U, et al: Spontaneous canine mammary tumors. A model for monoclonal antibody diagnosis and treatment of human breast cancer. Lab Invest. 71:182–187. 1994.PubMed/NCBI
4	Phillips JC, Lembcke L and Chamberlin T: A novel locus for canine osteosarcoma (OSA1) maps to CFA34, the canine orthologue of human 3q26. Genomics. 96:220–227. 2010. View Article : Google Scholar : PubMed/NCBI
5	MacEwen EG: Spontaneous tumors in dogs and cats: models for the study of cancer biology and treatment. Cancer Metastasis Rev. 9:125–136. 1990. View Article : Google Scholar : PubMed/NCBI
6	Peleteiro M: Tumores mamários na cadela e na gata. Revista Portuguesa de Ciências Veterinárias. 89:10–29. 1994.
7	Andrade FH, Figueiroa FC, Bersano PR, Bissacot DZ and Rocha NS: Malignant mammary tumor in female dogs: environmental contaminants. Diagn Pathol. 5:452010. View Article : Google Scholar : PubMed/NCBI
8	Hamilton A and Hortobagyi G: Chemotherapy: what progress in the last 5 years? J Clin Oncol. 23:1760–1775. 2005. View Article : Google Scholar : PubMed/NCBI
9	Winer E, Gralow J, Diller L, et al: Clinical cancer advances 2008: major research advances in cancer treatment, prevention, and screening - a report from the American Society of Clinical Oncology. J Clin Oncol. 27:812–826. 2009. View Article : Google Scholar :
10	Hsiao YH, Chou MC, Fowler C, Mason JT and Man YG: Breast cancer heterogeneity: mechanisms, proofs, and implications. J Cancer. 1:6–13. 2010. View Article : Google Scholar : PubMed/NCBI
11	Yuan L, Collins AR, Dai J, Dubocovich ML and Hill SM: MT(1) melatonin receptor overexpression enhances the growth suppressive effect of melatonin in human breast cancer cells. Mol Cell Endocrinol. 192:147–156. 2002. View Article : Google Scholar : PubMed/NCBI
12	Maganhin CC1, Carbonel AA, Hatty JH, et al: Melatonin effects on the female genital system: a brief review. Rev Assoc Med Bras. 54:267–271. 2008.(In Portuguese). View Article : Google Scholar : PubMed/NCBI
13	Luchetti F, Canonico B, Betti M, et al: Melatonin signaling and cell protection function. FASEB J. 24:3603–3624. 2010. View Article : Google Scholar : PubMed/NCBI
14	Cos S and Sánchez-Barceló EJ: Melatonin, experimental basis for a possible application in breast cancer prevention and treatment. Histol Histopathol. 15:637–647. 2000.PubMed/NCBI
15	Neto J and Scaldaferri P: Melatonina e câncer - revisão da literatura. Revista Brasileira Cancerol. 51:49–58. 2005.(In Portuguese).
16	Jablonska K, Pula B, Zemla A, et al: Expression of melatonin receptor MT1 in cells of human invasive ductal breast carcinoma. J Pineal Res. 54:334–345. 2013. View Article : Google Scholar : PubMed/NCBI
17	Mediavilla MD, Sanchez-Barcelo EJ, Tan DX, Manchester L and Reiter RJ: Basic mechanisms involved in the anti-cancer effects of melatonin. Curr Med Chem. 17:4462–4481. 2010. View Article : Google Scholar : PubMed/NCBI
18	Sturgeon SR, Doherty A, Reeves KW, et al: Urinary levels of melatonin and risk of postmenopausal breast cancer: Women’s health initiative observational cohort. Cancer Epidemiol Biomarkers Prev. 23:629–637. 2014. View Article : Google Scholar : PubMed/NCBI
19	Sanchez-Barcelo EJ, Mediavilla MD, Alonso-Gonzalez C and Rueda N: Breast cancer therapy based on melatonin. Recent Pat Endocr Metab Immune Drug Discov. 6:108–116. 2012. View Article : Google Scholar : PubMed/NCBI
20	Bejarano I, Espino J, Barriga C, Reiter RJ, Pariente JA and Rodríguez AB: Pro-oxidant effect of melatonin in tumour leucocytes: relation with its cytotoxic and pro-apoptotic effects. Basic Clin Pharmacol Toxicol. 108:14–20. 2011. View Article : Google Scholar
21	Rodriguez C, Martín V, Herrera F, et al: Mechanisms involved in the pro-apoptotic effect of melatonin in cancer cells. Int J Mol Sci. 14:6597–6613. 2013. View Article : Google Scholar : PubMed/NCBI
22	Cucina A, Proietti S, D’Anselmi F, et al: Evidence for a biphasic apoptotic pathway induced by melatonin in MCF-7 breast cancer cells. J Pineal Res. 46:172–180. 2009. View Article : Google Scholar : PubMed/NCBI
23	Eck KM, Yuan L, Duffy L, et al: A sequential treatment regimen with melatonin and all-trans retinoic acid induces apoptosis in MCF-7 tumour cells. Br J Cancer. 77:2129–2137. 1998. View Article : Google Scholar : PubMed/NCBI
24	Blask DE, Sauer LA and Dauchy RT: Melatonin as a chronobiotic/anticancer agent: cellular, biochemical, and molecular mechanisms of action and their implications for circadian-based cancer therapy. Curr Top Med Chem. 2:113–132. 2002. View Article : Google Scholar : PubMed/NCBI
25	Hardeland R, Pandi-Perumal SR and Cardinali DP: Melatonin. Int J Biochem Cell Biol. 38:313–316. 2006. View Article : Google Scholar
26	Lai L, Yuan L, Cheng Q, Dong C, Mao L and Hill SM: Alteration of the MT1 melatonin receptor gene and its expression in primary human breast tumors and breast cancer cell lines. Breast Cancer Res Treat. 118:293–305. 2009. View Article : Google Scholar
27	Grant SG, Melan MA, Latimer JJ and Witt-Enderby PA: Melatonin and breast cancer: cellular mechanisms, clinical studies and future perspectives. Expert Rev Mol Med. 11:e52009. View Article : Google Scholar : PubMed/NCBI
28	Misdorp W, Else R, Hellmen E and Lipscomb E: Definitions and explanatory notes. Who Histological Classification of Mammary Tumors of the Dog and Cat. Armed Forces Institute of Pathology; Washington: pp. 18–27. 1999
29	Cassali G, Bertagnolli A, Lavalle G, et al: Perpectives for diagnosis, prognosis and treatment of mammary neoplasms in dogs. In: 34th World Small Animal Veterinary Congress - WSAVA; São Paulo. 2009
30	Li XR, Liu M, Zhang YJ, et al: ER, PgR, HER-2, Ki-67, topoisomerase IIα, and nm23-H1 proteins expression as predictors of pathological complete response to neoadjuvant chemotherapy for locally advanced breast cancer. Med Oncol. 28(Suppl 1): S48–S54. 2011. View Article : Google Scholar
31	Livak K and Schimittgen T: Analyzing real-time PCR data by the comparative C(T) method. Nature Protocols. 3:1101–1108. 2008. View Article : Google Scholar : PubMed/NCBI
32	Jung JW, Park SB, Lee SJ, Seo MS, Trosko JE and Kang KS: Metformin represses self-renewal of the human breast carcinoma stem cells via inhibition of estrogen receptor-mediated OCT4 expression. PLoS One. 6:e280682011. View Article : Google Scholar : PubMed/NCBI
33	Rato AG, Pedrero JG, Martinez MA, del Rio B, Lazo PS and Ramos S: Melatonin blocks the activation of estrogen receptor for DNA binding. FASEB J. 13:857–868. 1999.PubMed/NCBI
34	Mao L, Cheng Q, Guardiola-Lemaître B, et al: In vitro and in vivo antitumor activity of melatonin receptor agonists. J Pineal Res. 49:210–221. 2010. View Article : Google Scholar : PubMed/NCBI
35	Leman ES, Sisken BF, Zimmer S and Anderson KW: Studies of the interactions between melatonin and 2 Hz, 0.3 mT PEMF on the proliferation and invasion of human breast cancer cells. Bioelectromagnetics. 22:178–184. 2001. View Article : Google Scholar : PubMed/NCBI
36	Sánchez-Hidalgo M, Guerrero JM, Villegas I, Packham G and de la Lastra CA: Melatonin, a natural programmed cell death inducer in cancer. Curr Med Chem. 19:3805–3821. 2012. View Article : Google Scholar : PubMed/NCBI
37	Wang J, Xiao X, Zhang Y, et al: Simultaneous modulation of COX-2, p300, Akt, and Apaf-1 signaling by melatonin to inhibit proliferation and induce apoptosis in breast cancer cells. J Pineal Res. 53:77–90. 2012. View Article : Google Scholar : PubMed/NCBI
38	Oprea-Ilies G, Haus E, Sackett-Lundeen L, et al: Expression of melatonin receptors in triple negative breast cancer (TNBC) in African American and Caucasian women: relation to survival. Breast Cancer Res Treat. 137:677–687. 2013. View Article : Google Scholar :
39	Collins A, Yuan L, Kiefer TL, Cheng Q, Lai L and Hill SM: Overexpression of the MT1 melatonin receptor in MCF-7 human breast cancer cells inhibits mammary tumor formation in nude mice. Cancer Lett. 189:49–57. 2003. View Article : Google Scholar
40	Hill SM, Blask DE, Xiang S, et al: Melatonin and associated signaling pathways that control normal breast epithelium and breast cancer. J Mammary Gland Biol Neoplasia. 16:235–245. 2011. View Article : Google Scholar : PubMed/NCBI
41	Gonzalez-Angulo AM, Morales-Vasquez F and Hortobagyi GN: Overview of resistance to systemic therapy in patients with breast cancer. Adv Exp Med Biol. 608:1–22. 2007. View Article : Google Scholar : PubMed/NCBI
42	Ram PT, Kiefer T, Silverman M, Song Y, Brown GM and Hill SM: Estrogen receptor transactivation in MCF-7 breast cancer cells by melatonin and growth factors. Mol Cell Endocrinol. 141:53–64. 1998. View Article : Google Scholar : PubMed/NCBI