Additional Roles of A-MSH/MC1R Signaling in Melanomagenesis Beyond Melanogenesis

Skin color is determined by epidermal melanin content, the function of which remains poorly understood. Clinically, there is a lower incidence of melanoma in individuals with high levels of constitutive brown/black pigment and/or acquired pigmentation (i.e. tanning). Conversely, individuals with red hair, blue eyes, and inability to tan are at higher risk for developing melanoma. Therefore, pigmentation represents a two-edged sword, with brown/black pigment (eumelanin) being protective and reddish pigment (pheomelanin) predisposing to melanoma [1,2]. However, the lower incidence of melanoma in albinos compared to individuals with red hair/fair skin underscores the complexity of the role of pigmentation in melanoma development. Together, there is essentially one key question of clinical significance to be addressed: why are red-haired individuals so prone to developing melanoma?