Evaluation of melatonin and AFMK levels in women with breast cancer
Changes in the circadian rhythm may contribute to the development of cancer and are correlated with the high risk of breast cancer (BC) in night workers. Melatonin is a hormone synthesized by the pineal gland at night in the absence of light. Levels of melatonin and the metabolite of oxidative metabolism AFMK (acetyl-N-formyl-5-methoxykynurenamine), are suggested as potential biomarkers of BC risk. The aims of this study were to evaluate levels of melatonin and AFMK in women recently diagnosed with BC, women under adjuvant chemotherapy, and night-shift nurses, and compare them with healthy women to evaluate the relation of these compounds with BC risk.
Blood samples were collected from 47 women with BC, 9 healthy women, 10 healthy night shift nurses, and 6 patients under adjuvant chemotherapy. Compound levels were measured by mass spectrometry.
Results and conclusions
Our results showed that women with BC had lower levels of melatonin compared to control group women, and even lower in night-shift nurses and in patients under adjuvant chemotherapy. There was no significant difference of AFMK levels between the groups. In addition to this, high levels of melatonin and AFMK were related to patients with metastasis, and high levels of AFMK were related to the presence of lymph node-positive, tumor > 20 mm and patients who sleep with light at night. Our results showed a reduction of melatonin levels in BC patients, suggesting a relation with the disease, and in addition, point to the importance of melatonin supplementation in women that work at night to reduce the BC risk.
KeywordsBreast cancer Circadian rhythmic Melatonin AFMK Blood level
We are grateful for the grant #2015/02935-2, from São Paulo Research Foundation (FAPESP), grant #003/2015, FAPERP—Foundation to Support Research and Extension of São José do Rio Preto and Professor Luis Albeto Beraldo de Moraes for ceding Spectrometry Laboratory of Pharmaceutical Sciences Faculty of Mass Ribeirão Preto—University of São Paulo to perform the analysis and thank Dr. Eduardo José Crevelin for the support.
All authors contributed significantly to the performance of work.
This study was funded by FAPESP—São Paulo Research Foundation (# 2015/02935-2) and FAPERP—Foundation to Support Research and Extension of São José do Rio Preto (Proc. 003/2015). This work was supported by the São Paulo Research Foundation (FAPESP) (grant #2015/02935-2).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 3.Z. Xie, F. Chen, W.A. Li, X. Geng, C. Li, X. Meng, Y. Feng, W. Liu, F. Yu, A review of sleep disorders and melatonin. Neurol. Res. 6412, 1 (2017)Google Scholar
- 4.Ja.S. Neto, B.F. De Castro, Melatonina, ritmos biológicos e sono –uma revisão da literatura. Rev. Bras. Neurol. 44, 5 (2008)Google Scholar
- 7.V. Srinivasan, G. Maestroni, D. Cardinali, A. Esquifino, S.P. Perumal, S. Miller, Melatonin, immune function and aging. Immun. Ageing 5, 109 (2011)Google Scholar
- 8.G. Ferry, C. Ubeaud, P.-H. Lambert, S. Bertin, F. Cogé, P. Chomarat, P. Delagrange, B. Serkiz, J.-P. Bouchet, R.J.W. Truscott, J.A. Boutin, Molecular evidence that melatonin is enzymatically oxidized in a different manner than tryptophan: Investigations with both indoleamine 2,3-dioxygenase and myeloperoxidase. Biochem. J. 388, 205 (2005)CrossRefPubMedPubMedCentralGoogle Scholar
- 10.J. Jaworek, J. Szklarczyk, J. Bonior, M. Kot, M. Goralska, P. Pierzchalski, R.J. Reiter, U. Czech, R. Tomaszewska, Melatonin metabolite, N1-acetyl-N1-formyl-5-methoxykynuramine (AFMK), attenuates acute pancreatitis in the rat: In vivo and in vitro studies. J. Physiol. Pharmacol. 67, 411 (2016)PubMedGoogle Scholar
- 14.R.J. Reiter, J.C. Mayo, D.X. Tan, R.M. Sainz, M. Alatorre-Jimenez, and L. Qin. Melatonin as an antioxidant: Under promises but over delivers. J. Pineal Res. 253, 253–278 (2016)Google Scholar
- 15.G.B. Gelaleti, T.F. Borin, L.B. Maschio-Signorini, M.G. Moschetta, B.V. Jardim-Perassi, G.B. Calvinho, M.C. Facchini, A.M. Viloria-Petit, D.A.P. de Campos Zuccari, Efficacy of melatonin, IL-25 and siIL-17B in tumorigenesis-associated properties of breast cancer cell lines. Life Sci. 183, 98 (2017)CrossRefPubMedGoogle Scholar
- 16.B.V. Jardim-Perassi, M.R. Lourenço, G.M. Doho, I.H. Grígolo, G.B. Gelaleti, L.C. Ferreira, T.F. Borin, M.G. Moschetta, D.A. Pires de Campos Zuccari, Melatonin regulates angiogenic factors under hypoxia in breast cancer cell lines. Anticancer Agents Med. Chem. 16, 347 (2016)CrossRefPubMedGoogle Scholar
- 17.T.F. Borin, A.S. Arbab, G.B. Gelaleti, L.C. Ferreira, M.G. Moschetta, B.V. Jardim-Perassi, A. Iskander, N.R.S. Varma, A. Shankar, V.B. Coimbra, V.A. Fabri, J.G. de Oliveira, D.A.P. de C. Zuccari, Melatonin decreases breast cancer metastasis by modulating rho-associated kinase protein-1 expression. J. Pineal Res. 60, 3 (2016)CrossRefPubMedGoogle Scholar
- 19.K. Straif, R. Baan, Y. Grosse, B. Secretan, F. El Ghissassi, V. Bouvard, A. Altieri, L. Benbrahim-Tallaa, V. Cogliano; WHO International Agency For Research on Cancer Monograph Working Group, Carcinogenicity of shift-work, painting, and fire-fighting. Lancet Oncol. 8, 1065 (2007)CrossRefPubMedGoogle Scholar
- 26.L. Tamarkin, D. Danforth, A. Lichter, E. DeMoss, M. Cohen, B. Chabner, M. Lippman, Decreased nocturnal plasma melatonin peak in patients with estrogen receptor positive breast. Cancer Sci. 216, 1003 (1982)Google Scholar
- 32.J.J. Gooley, K. Chamberlain, K.A. Smith, S.B.S. Khalsa, S.M.W. Rajaratnam, E. Van Reen, J.M. Zeitzer, C.A. Czeisler, S.W. Lockley, Exposure to room light before bedtime suppresses melatonin onset and shortens melatonin duration in humans. J. Clin. Endocrinol. Metab. 96, E463 (2011)CrossRefPubMedGoogle Scholar
- 33.E. Cordina-Duverger, F. Menegaux, A. Popa, S. Rabstein, V. Harth, B. Pesch, T. Brüning, L. Fritschi, D.C. Glass, J.S. Heyworth, T.C. Erren, G. Castaño-Vinyals, K. Papantoniou, A. Espinosa, M. Kogevinas, A. Grundy, J.J. Spinelli, K.J. Aronson, P. Guénel. Night shift work and breast cancer: A pooled analysis of population-based case–control studies with complete work history. Eur. J. Epidemiol. 1, 1–11 (2018)Google Scholar
- 35.S.M. Hill, C. Cheng, L. Yuan, L. Mao, R. Jockers, B. Dauchy, T. Frasch, D.E. Blask, Declining melatonin levels and MT1 receptor expression in aging rats is associated with enhanced mammary tumor growth and decreased sensitivity to melatonin. Breast Cancer Res. Treat. 127, 91 (2011)CrossRefPubMedGoogle Scholar
- 36.R.T. Dauchy, S. Xiang, L. Mao, S. Brimer, M.A. Wren, L. Yuan, M. Anbalagan, A. Hauch, T. Frasch, B.G. Rowan, D.E. Blask, S.M. Hill, Circadian and melatonin disruption by exposure to light at night drives intrinsic resistance to tamoxifen therapy in breast cancer. Cancer Res. 74, 4099 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
- 37.D.E. Blask, D.B. Pelletier, S.M. Hill, A. Lemus-Wilson, D.S. Grosso, S.T. Wilson, M.E. Wise, Pineal melatonin inhibition of tumor promotion in the N-nitroso-N-methylurea model of mammary carcinogenesis: Potential involvement of antiestrogenic mechanisms in vivo. J. Cancer Res. Clin. Oncol. 117, 526 (1991)CrossRefPubMedGoogle Scholar
- 38.P. Kubatka, B. Bojková, K. Môciková-Kalická, M. Mníchová-Chamilová, E. Adámeková, I. Ahlers, E. Ahlersová, M. Čermáková, Effects of tamoxifen and melatonin on mammary gland cancer induced by N-methyl-N-nitrosourea and by 7,12-dimethylbenz(a)anthracene, respectively, in female sprague-dawley rats. Folia Biol. (Praha) 47, 5 (2001)Google Scholar
- 39.N. do, N. Gonçalves, J. Colombo, J.R. Lopes, G.B. Gelaleti, M.G. Moschetta, N.M. Sonehara, E. Hellmén, C. de, F. Zanon, S.M. Oliani, D.A.P. de C. Zuccari, Effect of melatonin in epithelial mesenchymal transition markers and invasive properties of breast cancer stem cells of canine and human cell lines. PLoS ONE 11, e0150407 (2016)CrossRefGoogle Scholar
- 41.P. Orendáš, P. Kubatka, B. Bojková, M. Kassayová, K. Kajo, D. Výbohová, P. Kružliak, M. Péč, M. Adamkov, A. Kapinová, K. Adamicová, V. Sadloňová, M. Chmelová, N. Stollárová, Melatonin potentiates the anti-tumour effect of pravastatin in rat mammary gland carcinoma model. Int. J. Exp. Pathol. 95, 401 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
- 54.P. Terness, T.M. Bauer, L. Röse, C. Dufter, A. Watzlik, H. Simon, G. Opelz, Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: Mediation of suppression by tryptophan metabolites. J. Exp. Med. 196, 447 (2002)CrossRefPubMedPubMedCentralGoogle Scholar
- 58.A. Leja-Szpak, P. Pierzchalski, M. Goralska, K. Nawrot-Porabka, J. Bonior, P. Link-Lenczowski, M. Jastrzebska, J. Jaworek, Kynuramines induce overexpression of heat shock proteins in pancreatic cancer cells via 5-hydroxytryptamine and MT1/MT2 receptors. J. Physiol. Pharmacol. 66, 711 (2015)PubMedGoogle Scholar