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 (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.
Highlights
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
We reported the transcriptional reprogramming of N/Tert-1 cells by human papillomavirus 16 (HPV16) (N/Tert-1ϩHPV16) and demonstrate here that the growth of these cells is attenuated by estrogen while control parental N/Tert-1 cell growth was not affected by estrogen treatment
These studies demonstrated that increased levels of ER␣ predicted better survival, suggesting that this receptor may be of diagnostic significance and that estrogen could be a novel therapeutic for targeting HPVϩHNSCC [20, 21]
Summary
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. Using data from The Cancer Genome Atlas (TCGA), we and others determined that the estrogen receptor alpha (ER␣) is overexpressed in HPVϩHNSCC 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 HPVϩcancers. The role of estrogen in the development of head and neck cancer in these transgenic mouse models has not been reported In contrast to these results, studies demonstrate that high expression of estrogen receptor alpha (ER␣) correlates with increased survival in HPVϩHNSCC [20, 21]. The results demonstrate that estrogen attenuates the growth of HPV16ϩ keratinocytes and HPVϩ cancer cells and that there are potentially dual mechanisms for this attenuation: repression of viral transcription via targeting of the LCR and cellular reprograming of the host by E6/E7 that promotes the estrogen sensitivity.
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