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 2 decades, and therapeutic options for this ongoing health crisis are a priority; currently, there are no
antiviral therapeutics available for combatting HPV+cancers. During our TGCA studies on
head and neck cancer, we had also discovered the overexpression of ERα 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 human
telomerase reverse transcriptase [hTERT]) containing human papillomavirus 16 (HPV16) have elevated levels of ERα and growth sensitivity after
estrogen treatment compared with parental N/Tert-1 cells. 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.IMPORTANCE Human papillomaviruses cause around 5% of all human
cancers, yet there are no specific
antiviral therapeutic approaches available for combatting these
cancers. These
cancers are currently treated with standard chemoradiation
therapy (CRT). Specific
antiviral reagents are desperately required, particularly for HPV+HNSCC whose incidence is increasing and for which there are no diagnostic tools available for combatting this disease. Using data from The
Cancer Genome Atlas (TCGA), we and others determined that the
estrogen receptor alpha (ERα) 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 combatting 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.