Some

MC1R

variants are associated with an increased risk of melanoma. Due to increased sun sensitivity and freckling of people with pale skin, this relationship seems obvious. However,

darkly pigmented Caucasians with certain

MC1R variants also show an increased incidence of melanoma. This result suggests that the MC1R pathway may have another role in the development of melanoma beyond differences in the ability to filter UV rays in light and dark skin. In fact, scientists think that

MC1R may play a pigment-dependent and a pigment-independent role in skin carcinogenesis. There are a few hypotheses to explain the link

between MC1R and melanoma. First,

after UV exposure, cells with more , which is correlated with increases in abnormal cell growth and proliferation, a hallmark of cancer. Second, a recent paper in pheomelanin show increases in DNA damage , which is correlated with increases in abnormal cell growth and proliferation, a hallmark of cancer. Second, a recent paper in

Molecular Cell

suggested that UV light triggers the interaction of a tumor suppressor called PTEN with MC1R. The tumor suppressor can interact with wild type MC1R, but not the red hair alleles of MC1R. The PTEN-MC1R interaction protects PTEN from degradation, which suppresses an oncogenic signaling pathway (PI3K/Akt). In contrast,

MC1R variants do not interact with PTEN, allowing increased levels of oncogenic signaling pathways after UV irradiation. Unfortunately for redheads, sun exposure alone is not the sole mechanism for skin cancer. A

Nature

paper from

David Fisher’s lab

used a red-head mouse model with inactive

MC1R

to investigate a possible UV-independent pathway. They found that in the presence of the most common melanoma oncoprotein (BRAF 600E), ginger mice developed melanoma without UV exposure, while MC1R wild-type mice did not. Thus, shielding easily freckled skin from the sun may not be enough to protect from skin cancer for people with certain MC1R variants.