Therapeutic Potential of Nitric Oxide releasing Selective Estrogen Receptor Modulators (NO-SERMs) in Malignant Melanoma

Malignant melanoma has a steadily increasing incidence, but treatment options are still limited and prognosis for patients, especially for men, is poor. To investigate whether targeting estrogen receptor (ER) signaling is a valid therapeutic approach, we retrospectively analyzed ER gene expression profiles in 448 melanoma patients. High ERα gene expression was associated with improved overall survival (HR=0.881; 95% Cl=0.793-0.979, p=0.018) and increased with tumor stage, while ERβ gene expression did not change with tumor progression. This seemingly protective function of ERα led us to speculate that specific targeting of ERβ has a therapeutic benefit in malignant melanoma. A new type of ERβ-selective ER modulator with a nitric oxide (NO•) releasing moiety (NO-SERM 4d) significantly reduced the pro-metastatic behavior of two melanoma cell lines (A2058 and MelJuso). Epithelial-mesenchymal transition in melanoma is consistent with a switch from E- to N-cadherin expression, mediating the invasive phenotype. NO-SERM 4d reduced N-cadherin expression and impaired spheroid formation in A2058 cells. In addition, growth of A2058 spheroids was significantly reduced, confirming the anti-tumorigenic potential of NO-SERM 4d. Targeting ERβ signaling combined with targeted NO• release represents a promising therapeutic approach in malignant melanoma that has potential to prevent metastatic spread and reduce tumor growth.