Estrogen Receptor β in Melanoma: From Molecular Insights to Potential Clinical Utility

Abstract

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.

Menopausal hormone therapy and risk of melanoma: Do estrogens and progestins have a different role?

“…Estrogen receptor beta (ERβ) is the predominant estrogen receptor in melanoma cells. Its expression was reported to decrease with increasing depth of invasion and progression and therefore ERβ was hypothesized to have an antitumor activity in SMM . ERβ has also been considered as a possible molecular target for melanoma treatment.…”

“…Its expression was reported to decrease with increasing depth of invasion and progression and therefore ERb was hypothesized to have an antitumor activity in SMM. [20][21][22] ERb has also been considered as a possible molecular target for melanoma treatment. A metaanalysis of nine randomized clinical trials comparing chemotherapy with Tamoxifen, which is an estrogen antagonist, to chemotherapy alone in metastatic SMM patients showed that chemotherapy with Tamoxifen improved overall and partial response, especially in women, but did not improve mortality in 1 year.…”

Genetic variants in RORA and DNMT1 associated with cutaneous melanoma survival

“…1 Referring to reference allele/effect allele. 2 Adjusted for age, sex, Breslow thickness, distant/regional metastasis, ulceration and mitotic rate in Cox models of SNPs and melanoma-specific survival in MDACC study and all the tests of the proportional hazards assumption for the validated SNPs were not significant (p > 0.05). 3 Adjusted for age and sex in Harvard study.…”

“…1 Adjusted for age, sex, Breslow thickness, distant/regional metastasis, ulceration and mitotic rate in Cox models of SNPs and CMSS in MDACC study. 2 Adjusted for age and sex in Harvard study. 3…”

“…11 In addition, clinical studies have showed that ERb has been reported as a predominant ER subtype in melanoma as a most important prognostic factor, and its expression negatively correlate with melanoma growth and progression. 2 Furthermore, the loss of the ERb protein in melanoma is directly proportional to Breslow thickness. 12 ERb was more frequently expressed in the melanomas of women [both pregnant and non-pregnant] than in those of men.…”