Estrogen attenuates the growth of human papillomavirus positive epithelial cells

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 (ERα) 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 ERa in HPV+cancers. Here we demonstrate that 17β-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 ERα 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.