Influence of melatonin on invasive and metastatic properties of MCF-7 human breast cancer cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 1998-10, Vol.58 (19), p.4383-4390
• Main Authors: COS, S, FERNANDEZ, R, GÜEZMES, A, SANCHEZ-BARCELO, E. J
• Format: Article
• Language: English
• Subjects: Adipose Tissue; Animals; Antineoplastic Agents; Basement Membrane; Biological and medical sciences; Breast Neoplasms - pathology; Breast Neoplasms - physiopathology; Cadherins - biosynthesis; Cell Adhesion - drug effects; Cell Division; Chemotaxis - drug effects; Chemotaxis - physiology; Collagenases - metabolism; Culture Media, Conditioned; Estradiol - pharmacology; Female; Gynecology. Andrology. Obstetrics; Humans; Integrin beta1 - biosynthesis; Mammary gland diseases; Mammary Glands, Animal; Matrix Metalloproteinase 9; Medical sciences; Melatonin - pharmacology; Melatonin - physiology; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Tumors; Vimentin - biosynthesis
• ISSN: 0008-5472; 1538-7445

Melatonin, the principal pineal gland hormone, exerts a direct antiproliferative effect on estrogen-responsive MCF-7 cells in culture. The purpose of the current study was to investigate the effects of melatonin on the invasion capacity of MCF-7 cells. In vitro, melatonin at physiological doses (1 nM) reduced (P < 0.001) the invasiveness of tumoral cells measured in Falcon invasion chambers. Subphysiological (0.1 pM) and pharmacological concentrations (10 microM) of melatonin failed to inhibit cell invasion. Melatonin was also able to block 17beta-estradiol-induced invasion (P < 0.001). Pretreatment of MCF-7 cells with 1 nM melatonin increased the response of tumoral cells to the anti-invasive effects of this indolamine. To explore possible mechanisms by which melatonin reduces invasiveness, we measured the attachment of MCF-7 cells to a basement membrane, the chemotactic response of the cells, and their type IV collagenolytic activity. The presence of melatonin (1 nM) in the culture medium significantly reduced the ability of MCF-7 cells to attach to the basement membrane; this effect was enhanced by pretreating the cells with the same indolamine (P < 0.001). Melatonin also counteracts the stimulatory effects of 17beta-estradiol on cell adhesion (P < 0.001). The chemotactic response of MCF-7 cells also decreased in the presence of 1 nM melatonin, and this melatonin-induced reduction of cell migration was more effective on cells that were previously incubated for 5 days with melatonin than it was on nonpretreated cells (P < 0.001). The simultaneous addition of 17beta-estradiol and melatonin resulted in a significantly lower chemotactic response than that of 17beta-estradiol-treated cells (P < 0.001). However, type IV collagenolytic activity was not influenced by melatonin. Our results demonstrate that melatonin reduces the invasiveness of MCF-7 cells, causing a decrease in cell attachment and cell motility, probably by interacting with the estrogen-mediated mechanisms of MCF-7 cell invasiveness. In addition, we also studied the influence of melatonin on the expression of two cell surface adhesion molecules (E-cadherin and beta1 integrin) and an intermediate filament protein (vimentin), the expression of which has been correlated with the relative invasive capacity of human breast cancer cells. The culture of tumor cells in the presence of melatonin (1 nM) increased the membrane staining for E-cadherin and beta1 integrin as well as the number of E-cadherin