Human malignant melanoma is a very aggressive human cancer its incidence has been found to increase faster than any other cancer during the past decades importantly, it is one of the most frequent cancers in adolescents and young adults ( 1). A better identification of the role of ERβ in melanoma development will help increase the therapeutic options for this aggressive pathology. Importantly, these effects are unrelated to the oncogenic mutations of melanomas, suggesting that, in addition to their ERβ activating function, these compounds might impair melanoma development through additional mechanisms.

These phytoestrogens decrease the proliferation of melanoma cells. Natural compounds that specifically bind to ERβ have been identified. In an era of personalized medicine, pretreatment evaluation of the expression of ER isoforms together with the concurrent oncogenic mutations should be considered before selecting the most appropriate therapeutic intervention. These data suggest that ERβ agonists might be considered as an effective treatment strategy, in combination with MAPK inhibitors, for NRAS mutant melanomas. In vitro studies demonstrate that ERβ ligands inhibit the proliferation of melanoma cells harboring the NRAS (but not the BRAF) mutation, suggesting that ERβ activation might impair melanoma development through the inhibition of the PI3K/Akt pathway. 17β-estradiol was reported to inhibit melanoma cells proliferation however, clinical trials did not provide the expected survival benefits. Thus, ERβ is now considered as an effective molecular target for melanoma treatment. ERβ is the predominant ER in melanoma, and its expression decreases in melanoma progression, supporting its role as a tumor suppressor. Estrogens exert their effects through estrogen receptors (ERα and ERβ) that affect cancer growth in an opposite way: ERα is associated with a proliferative action and ERβ with an anticancer effect. Melanoma incidence is higher in males than in females, and females have a significant survival advantage over men. Increasing evidence supports that melanoma is a hormone-related cancer. However, treatment resistance and side effects are common events of these therapeutic strategies. The current therapeutic approaches are based on therapies targeting mutated BRAF and the downstream pathway, and on monoclonal antibodies against the immune checkpoint blockade.

Melanoma is a heterogeneous tumor, with most patients harboring mutations in the BRAF or NRAS oncogenes, leading to the overactivation of the MAPK/ERK and PI3K/Akt pathways. 2Department of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano, Milano, ItalyĬutaneous melanoma is an aggressive tumor its incidence has been reported to increase fast in the past decades.1Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milano, Italy.Roberta Manuela Moretti 1 and Patrizia Limonta 1*

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