Effect of Melatonin on Tumor Growth and Angiogenesis in Xenograft Model of Breast Cancer Bruna Victorasso Jardim-Perassi, Ali S. Arbab,. Lívia Carvalho Ferreira, Thaiz Ferraz Borin, Nadimpalli R. S. Varma, A. S. M. Iskander, Adarsh Shankar,Meser M. Ali, Debora Aparecida Pires de Campos Zuccari
Abstract As neovascularization is essential for tumor growth and metastasis, controlling angiogenesis is a promising tactic in limiting cancer progression. Melatonin has been studied for their inhibitory properties on angiogenesis in cancer. We performed an in vivo study to evaluate the effects of melatonin treatment on angiogenesis in breast cancer. Cell viability was measured by MTT assay after melatonin treatment in triple-negative breast cancer cells (MDA-MB-231). After, cells were implanted in athymic nude mice and treated with melatonin or vehicle daily, administered intraperitoneally 1 hour before turning the room light off. Volume of the tumors was measured weekly with a digital caliper and at the end of treatments animals underwent single photon emission computed tomography (SPECT) with Technetium-99m tagged vascular endothelial growth factor (VEGF) C to detect in vivo angiogenesis. In addition, expression of pro-angiogenic/growth factors in the tumor extracts was evaluated by membrane antibody array and collected tumor tissues were analyzed with histochemical staining. Melatonin in vitro treatment (1 mM) decreased cell viability (p<0.05). The breast cancer xenografts nude mice treated with melatonin showed reduced tumor size and cell proliferation (Ki-67) compared to control animals after 21 days of treatment (p<0.05). Expression of VEGF receptor 2 decreased significantly in the treated animals compared to that of control when determined by immunohistochemistry (p<0.05) but the changes were not significant on SPECT (p>0.05) images. In addition, there was a decrease of micro-vessel density (Von Willebrand Factor) in melatonin treated mice (p<0.05). However, semiquantitative densitometry analysis of membrane array indicated increased expression of epidermal growth factor receptor and insulin-like growth factor 1 in treated tumors compared to vehicle treated tumors (p<0.05). In conclusion, melatonin treatment showed effectiveness in reducing tumor growth and cell proliferation, as well as in the inhibition of angiogenesis.
Background: Melatonin seems to play a role in breast cancer etiology, but data addressing the association between melatonin levels and breast cancer risk in postmenopausal women is sparse.
Methods: We conducted a nested case-control study in the Nurses' Health Study cohort. First spot morning urine was collected from 18,643 cancer-free women from March 2000 through December 2002. The concentration of the major metabolite of melatonin, 6-sulfatoxymelatonin (aMT6s), was available for 357 postmenopausal women who developed incident breast cancer through May 31, 2006, along with 533 matched control subjects. We used multivariable conditional logistic regression models to investigate associations. All statistical tests were two sided.
Results: An increased concentration of urinary aMT6s was statistically significantly associated with a lower risk of breast cancer (odds ratio for the highest versus lowest quartile of morning urinary aMT6s, 0.62; 95% confidence interval, 0.41-0.95; Ptrend = 0.004). There was no apparent modification of risk by hormone receptor status of breast tumors, age, body mass index, or smoking status.
Conclusion: Results from this prospective study add substantially to the growing literature that supports an inverse association between melatonin levels and breast cancer risk.