We recently demonstrated that mice lacking the epidermal
glucocorticoid (GC) receptor (GR) (GR epidermal knockout (GR(
EKO)) mice) have developmental defects and sensitivity to epidermal challenge in adulthood. We examined the susceptibility of GR(
EKO) mice to skin chemical
carcinogenesis. GR(
EKO) mice treated with a low dose of 12-dimethylbenz(a)
anthracene (DMBA) followed by
phorbol 12-myristate 13-acetate (PMA) promotion exhibited earlier
papilloma formation with higher incidence and multiplicity relative to control littermates (CO). Augmented proliferation and
inflammation and defective differentiation of GR(
EKO) keratinocytes contributed to the phenotype, likely through increased AKT and STAT3 (
signal transducer and activator of transcription 3) activities. GR(
EKO)
tumors exhibited signs of early malignization, including delocalized expression of
laminin A, dermal invasion of
keratin 5 (K5)-positive cells, K13 expression, and focal loss of
E-cadherin. Cultured GR(
EKO) keratinocytes were spindle like, with loss of
E-cadherin and upregulation of smooth muscle actin (SMA) and Snail, suggesting partial epithelial-mesenchymal transition. A high DMBA dose followed by PMA promotion generated sebaceous
adenomas and melanocytic foci in GR(
EKO) and CO. Importantly, the number, growth kinetics, and extent of both
tumor types increased in GR(
EKO) mice, suggesting that in addition to regulating
tumorigenesis from epidermal lineages, GR in keratinocytes is important for cross-talk with other skin cells. Altogether, our data reinforce the importance of GR in the pathogenesis of
skin cancer.