Estrogen attenuates the growth of human papillomavirus positive epithelial cells

Abstract

Human papillomaviruses (HPVs) are small, double-stranded DNA viruses that are significant risk factors in the development of cancer, and HPV accounts for approximately 5% of all worldwide cancers. Recent studies using data from The Cancer Genome Atlas (TCGA) have demonstrated that elevated levels of estrogen receptor alpha (ER) are associated with improved survival in oropharyngeal cancers, and these elevated receptor levels were linked with human papillomavirus positive cancers (HPV+cancers). There has been a dramatic increase in HPV-related head and neck squamous cell carcinomas (HPV+HNSCCs) over the last two decades and therapeutic options for this ongoing health crisis are a priority; currently there are no anti-viral therapeutics available for combating HPV+cancers. During our own TGCA studies on head and neck cancer we had also discovered the overexpression of ER in HPV+cancers. Here we demonstrate that 17{beta}-estradiol (estrogen) attenuates the growth/cell viability of HPV+cancers in vitro, but not HPV negative cancer cells. In addition, N/Tert-1 cells (foreskin keratinocytes immortalized with hTERT) containing HPV16 have elevated levels of ER and growth sensitivity following estrogen treatment when compared with parental N/Tert-1. Finally, we demonstrate that there are potentially two mechanisms contributing to the attenuation of HPV+ cell growth following estrogen treatment. First, estrogen represses the viral transcriptional long control region (LCR) downregulating early gene expression, including E6/E7. Second, expression of E6 and E7 by themselves sensitizes cells to estrogen. Overall our results support the recent proposal that estrogen could be exploited therapeutically for the treatment of HPV positive oral cancers. ImportanceHuman papillomaviruses cause around 5% of all human cancers, yet there are no specific anti-viral therapeutic approaches available for combating these cancers. These cancers are currently treated with standard chemo-radiation therapy (CRT). Specific anti-viral reagents are desperately required, particularly for HPV+HNSCC whose incidence is increasing and for which there are no diagnostic tools available for combating this disease. Using data from The Cancer Genome Atlas (TCGA) ourselves and others determined that the estrogen receptor (ER) is overexpressed in HPV+HNSCC, and that elevated levels are associated with an improved disease outcome. This has led to the proposal that estrogen treatment could be a novel therapeutic approach for combating HPV+cancers. Here we demonstrate that estrogen attenuates the growth of HPV+epithelial cells using multiple mechanisms, supporting the idea that estrogen has potential as a therapeutic agent for the treatment of HPV+HNSCC.