Role of Estrogen receptor β against melanoma progression

Cutaneous melanoma is one of the most frequent and aggressive forms of malignant skin cancer. In agreement with its significant sex disparities, a number of studies indicated melanoma as a hormone sensitive cancer. Nevertheless, conflicting results have been produced so far about the action of steroid hormones, mainly estrogens. The effects of estradiol and its analogues are mediated by the Estrogen Receptors (ERs) α and β which play proliferative or antitumor activity, respectively. According to its protective role, ERβ expression level inversely correlates with tumor progression, as demonstrated in some primary and metastatic melanoma cell lines. 17β-Estradiol is the most active form of circulating estrogen and binds both ER isoforms. Indeed, treatment with elevated doses of 17β-estradiol caused a cell cycle block at the G2/M boundary only in those melanoma cells with higher ERβ/α ratio. In order to specifically induce ERβ signaling, we chose its selective agonist LY500307 (Erteberel), a synthetic non-steroidal estrogen, previously proposed as a treatment for glioblastoma. Results showed a substantial dose and time-dependent cell cycle block at G2/M boundary associated with aberrant mitotic structures apparently connected to mitotic catastrophe as the treatment was accompanied by pro-apoptotic signals, as increased Annexin/PI positive cells, caspase 3 activation and PARP cleavage. When compared BRAF- and NRAS-mutated melanoma cell lines an unexpected higher effectiveness in the last ones was observed. Ongoing studies will investigate if the mechanism of G2/M arrest and relative apoptosis program activation are consequences of an actual mitotic catastrophe. In particular, results obtained in NRAS mutated melanoma cell lines might open a new window for treatment of a mutational status still lacking effective target therapies. Moreover, these and further data on the antitumor efficacy of Erteberel will definitely attribute to ER the key role in the transmission of the beneficial hormonal effects in melanoma.