Expression of estrogen receptor alpha is associated with pathogenesis and prognosis of human papillomavirus‐positive oropharyngeal cancer

Human papillomavirus (HPV) has been identified as a causative agent of cervical cancer and oropharyngeal cancer (OPC). Intriguingly, estrogen and HPV were shown to play synergistic roles in cervical carcinogenesis. We recently demonstrated that the apolipoprotein B mRNA‐editing catalytic polypeptide 3 (APOBEC3, A3) family, which is inducible by estrogen, could lead to HPV DNA hypermutation and cause viral DNA integration. In the present study, we examined the relationships between estrogen–estrogen receptor α (ERα) and A3s in HPV‐positive OPC. ERα expression was associated with HPV positivity in OPC biopsy samples using immunohistochemical analysis and reverse‐transcription quantitative polymerase chain reaction. In addition, ERα was significantly associated with improved overall survival in HPV‐positive OPC (hazard ratio, 0.26; p = 0.029). APOBEC3A (A3A) mRNA was induced by estrogen in HPV and ERα‐positive OPC cells. Furthermore, A3A mRNA and protein expression were significantly higher in ERα‐positive cases than in ERα‐negative ones, among HPV‐positive biopsy samples (p = 0.037 and 0.047). These findings suggest that A3A is associated with a good prognosis in ERα‐positive OPC, and indicate the prognostic significance of ERα in HPV‐positive OPC. This is the first study to demonstrate the prognostic role of ERα in HPV‐positive OPC. What's new? Human papillomavirus (HPV) is a causative agent of cervical and oropharyngeal cancer (OPC). Intriguingly, HPV and estrogen play synergistic roles in cervical carcinogenesis. This is the first study to show the contribution of estrogen receptor (ER) signaling in HPV‐mediated OPC. ERα was associated with HPV positivity in OPC and was a favorable prognostic factor. In vitro, estrogen induced the expression of the apolipoprotein B mRNA‐editing catalytic polypeptide 3 A, and A3A was associated with ERα in biopsies. The findings reveal a close association among ERα, A3A, and survival in HPV‐related OPC and highlight ERα and A3A as potential prognostic markers.