Redheads be Warned

I’m a natural redhead.  As such, I tend to not make much in the way of skin pigment.  I have two skin colors: white and red.  There is no tan.  For years, especially when I was younger, people tried to convince me that I just needed to build a good base tan a little at a time.  Unfortunately, for me and many like me, that’s actually biologically impossible: the genes for “tanning” are broken.  I’ve been slathering on sunscreen for as long as I can remember (thanks, Mom!) but the title of this article startled me:

An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background

Apparently, what I’m doing may not be enough.  The title implies I can get melanoma WITHOUT going out into the sun (which I already avoid like the plague).  What’s a poor redhead to do?

I suppose first you need to understand how skin “tans” or makes pigment: what makes dark skin dark and light skin light?  The really short and simple version is basically something like this.  There are two types of melanin.  Eumelanin is the darker, tan/brown pigment.  Pheomelanin is the lighter pinkish/yellowish pigment.  Guess which ones redheads make more of?  Yep–pheomelanin.   Pheomelanin is made by the Tyr gene from tyrosine (an amino acid).

On the surface of your cells is a receptor called MC1R  (that stands for melanocortin-1 receptor).  When this receptor is stimulated (by certain hormones or UV damage), it triggers your skin to convert pheomelanin (red/yellow) into eumelanin (brown).   Most redheads with fair skin who always burn and never tan–that MC1R receptor is broken.  It’s mutated.  It doesn’t work.  So, our cells don’t really get the idea that they’re supposed to make pigment in the first place, and if they DO, it tends to be pheomelanin.  We can usually make eumelanin in spots (freckles).

Source:  Sturm RA, Box NF, Ramsay M (1998) Human pigmentation genetics: the difference is only skin deep. Bioessays 20:712-21.

Source: Sturm RA, Box NF, Ramsay M (1998) Human pigmentation genetics: the difference is only skin deep. Bioessays 20:712-21.

Biologically, melanin is supposed to help protect your cells from UV damage by acting sort of like a physical shield and blocking the UV, keeping it from hitting your DNA.  Pheomelanin isn’t as good at absorbing UV as eumelanin.  That’s just like any other pigment: the darker the color, the more light it absorbs (and the hotter it gets in the sun!).

So researchers made some redheaded mice by causing a mutation in the MC1R gene.  The mice don’t exactly look like redheads–maybe strawberry blondes?  They also made some albino mice that had broken versions of the Tyr gene–so these mice couldn’t even make pheomelanin.  Albino = no pigment at all.   They also added a gene to give melanoma-on-demand whenever they gave the mice the drug tamoxifen.

They treated young mice with the drug (by rubbing it on their skin for 5 days) and then left the mice alone to live their normal mousie lives.  The red mice started dying earlier than the black mice OR the albino mice.  In less than a year, over half the redheaded mice developed melanoma.  YIKES! The tumors were pretty much the same for all 3 types of mice, except for color-the black mice had some darker layers up near the surface of their tumors, but the redheaded and albino mice didn’t.  Mostly, it was just that the redheaded mice grew more melanomas.

Figure 1 | Without ultraviolet radiation, BrafCA red mice have an increased rate of melanoma development relative to black and albino BrafCA animals.

Figure 1 | Without ultraviolet radiation, BrafCA red mice have an increased rate of melanoma development relative to black and albino BrafCA animals.

What was really odd was what happened if they took out BOTH the MC1R gene AND the Tyr gene.  These mice were unable to make pheomelanin OR to convert it to eumelanin.  Oddly, that was protective: the mice survived pretty much like the regular albino mice did.  That means that the albino  mutation somehow protected the mice.  Does that mean that pheomelanin itself is pro-cancer?  This is an interesting idea, because people (and mice) with dark skin actually produce both types of melanin.  The authors wondered if the eumelanin was able to overcome the effects of the pheomelanin.  It’s an interesting idea–but I think that two things are important.  (1) Although both pigments are present, dark-skinned people have more eumelanin than pheomelanin: the ratio is very different.  That implies that the risk is also probably different; if you have less pheomelanin, wouldn’t your risk be lower?  That seems to be true for the dark mice (which have less pheomelanin) and the albino mice (which have no pheomelanin).  (2) Pheomelanin can be converted into eumelanin.  That’s part of what changes the ratio: it decreases the amount of phaeomelanin while simultaneously increasing the amount of eumelanin.  That’s sort of a double-whammy.

Figure 4 | The ultraviolet-radiation-independent propensity of red BrafCA mice to develop melanoma is dependent on pigment production.

Figure 4 | The ultraviolet-radiation-independent propensity of red BrafCA
mice to develop melanoma is dependent on pigment production.

More than that, they also found that the normal skin from redheaded mice had more DNA damage and lipid damage than even the albino mice.  These are signs of oxidative stress, and it’s one of the things that is thought to contribute to skin aging.  So these mice probably would have gotten older-looking faster than the other mice.  Exposure to UV light in redheaded mice just made the damage worse.

The take-home message for me is that I should get screened MUCH more carefully for melanoma, and that sunscreen is even more important than I thought; my skin not only  has no defense, but it seems to be predisposed toward melanoma!  Needless to say, none of this applies if your red hair is due to Clairol.  It’s genetic.

 

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