title: Rethinking tamoxifen in the management of melanoma: New answers for an old question.
abstract: The use of the antiestrogen tamoxifen in melanoma therapy is controversial due to the unsuccessful outcomes and a still rather unclarified mechanism of action. It seemed that the days of tamoxifen in malignant melanoma therapy were close to an end, but new evidence may challenge this fate. On one hand, it is now believed that metabolism is a major determinant of tamoxifen clinical outcomes in breast cancer patients, which is a variable that has yet to be tested in melanoma patients, since the tamoxifen active metabolite endoxifen demonstrated superior cytostatic activity over the parent drug in melanoma cells; on the other hand, new evidence has emerged regarding estrogen-mediated signaling in melanoma cells, including the methylation of the estrogen receptor-α gene promoter and the expression of the G protein coupled estrogen receptor. The expression of estrogen receptor-α and G protein coupled estrogen receptor, as well as the cytochrome P450 (CYP) 2D6 genotype, may be used as predictive biomarkers to select the patients that may respond to antiestrogens based on specific traits of their tumors. This review focused on these new evidences and how they may contribute to shed new light on this long-lasting controversy, as well as their possible implications for future investigations.
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal; Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal. Electronic address: marianaponte@msn.com.
authors.forename: Mariana P C
authors.initials: MPC
authors.lastname: Ribeiro
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal; Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: Armanda E
authors.initials: AE
authors.lastname: Santos
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal; Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: José B A
authors.initials: JBA
authors.lastname: Custódio
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D004965:Estrogen Antagonists / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013629:Tamoxifen / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; C109584:GPER1 protein, human; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D013629:Tamoxifen; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6
keywords: Endoxifen; Estrogen receptor α; G protein coupled estrogen receptor; Melanoma; Tamoxifen metabolism