The inactivity of estrogenic pathways, specifically those regulated by ER-β signaling, significantly reduced the protective actions of topical 1,25(OH)2D against these critical cutaneous responses that might otherwise act to protect the skin from the initial steps towards skin cancer development and correlates with the relative insensitivity to 1,25(OH)2D photoprotection and greater skin cancer susceptibility known to prevail in the male sex. Here, ESR2 is linked to skin cancer.