Cutaneous
melanoma is an aggressive
tumor; its incidence has been reported to increase fast in the past decades.
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. The current therapeutic approaches are based on
therapies targeting mutated BRAF and the downstream pathway, and on
monoclonal antibodies against the
immune checkpoint blockade. However, treatment resistance and side effects are common events of these therapeutic strategies. Increasing evidence supports that
melanoma is a
hormone-related
cancer.
Melanoma incidence is higher in males than in females, and females have a significant survival advantage over men.
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. ERβ is the predominant ER in
melanoma, and its expression decreases in
melanoma progression, supporting its role as a
tumor suppressor. Thus, ERβ is now considered as an effective molecular target for
melanoma treatment. 17β-estradiol was reported to inhibit
melanoma cells proliferation; however, clinical trials did not provide the expected survival benefits. 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. These data suggest that ERβ agonists might be considered as an effective treatment strategy, in combination with MAPK inhibitors, for NRAS mutant
melanomas. 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. Natural compounds that specifically bind to ERβ have been identified. These
phytoestrogens decrease the proliferation of
melanoma cells. 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. A better identification of the role of ERβ in
melanoma development will help increase the therapeutic options for this aggressive pathology.