Estrogen receptor α ( <i>Esr1</i> ) mediates estrogen’s ability to promote papillomavirus-induced cutaneous disease in male and female mice

ABSTRACT Persistent papillomavirus infection is a key driver of neoplastic progression in both mucosal and cutaneous epithelia. Although estrogen is a well-established cofactor in HPV-associated cervical carcinogenesis, its role in cutaneous papillomavirus disease has remained poorly understood. Using a murine papillomavirus type 1 (MmuPV1) infection model in immunocompetent FVB/N mice, we investigated whether estrogen influences viral pathogenesis in infected cutaneous epithelia. Estrogen treatment significantly increased wart incidence and growth independent of sex and was associated with pronounced epithelial hyperplasia, dysplasia, koilocytosis, and features of invasive squamous cell carcinoma. Systemically, estrogen reduces circulating leukocytes, while locally suppressing adaptive immune infiltration and enriching neutrophils within lesions, indicating broad immunosuppression coupled with selective innate enhancement. MmuPV1 E1^E4 and L1 RNA and protein levels were elevated in warts of estrogen-treated WT mice, indicative of enhanced productive infection. Importantly, Esr1 germline knockout mice exhibited significantly reduced wart incidence and size in both males and females, lower MmuPV1 E1^E4 and L1 transcript levels, coupled with the absence of estrogen-induced depletion of circulating immune cells, demonstrating that ERα signaling mediates estrogen-driven epithelial proliferation, immune modulation, disease progression, and productive viral infection. Collectively, these novel findings indicate that estrogen is a potent cofactor in cutaneous papillomavirus disease, acting through ERα-dependent pathways to drive virally -induced neoplastic diseases, including cancer. IMPORTANCE Papillomaviruses are major causes of cancer in both women and men, yet the factors that influence disease severity remain incompletely understood. While estrogen is known to cooperate with papillomaviruses to drive cervical cancer, its role in papillomavirus-associated skin disease has not been defined. Our study demonstrates that estrogen significantly amplifies papillomavirus-induced skin pathology in both male and female mice, increasing the frequency, size, and severity of epidermal lesions. These findings reveal a previously unrecognized hormonal influence on cutaneous papillomavirus disease and suggest that sex hormones may broadly modulate papillomavirus-associated cancers beyond the reproductive tract.