Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model

Abstract

Cervical cancer is a leading cause of death by cancer among women worldwide. High-risk human papillomaviruses (HPVs) are the major etiological agents for cervical cancer, but other factors likely contribute to cervical cancer, because these cancers commonly arise decades after initial exposure to HPV. Estrogen is thought to be one such cofactor; however, its temporal requirements in human cervical cancer are not known. Here we evaluate the temporal requirements of estrogen in cervical carcinogenesis in a mouse model for HPV-associated cervical cancer. Tumors arising in HPV16 transgenic mice treated with estrogen for 9 months were greatly increased in their size compared with tumors developing after 6 months of estrogen treatment. HPV16 transgenic mice treated 6 months with estrogen followed by 3 months without exogenous estrogen had significantly fewer tumors and the tumors were smaller and less aggressive than those arising in mice treated the full 9 months. Importantly, cervical cancers that arose in the mice treated the first 6 of 9 months with estrogen must have regressed, based upon the reduced incidence of cancers in these mice compared with those treated for 6 months with estrogen, then immediately analyzed. We conclude that estrogen plays a critical role not only in the genesis of cervical cancer but also in its persistence and continued development in this mouse model. These findings raise the clinically relevant possibility that, if human cervical cancer has a similar dependence on estrogen for continued tumor growth, then antiestrogen therapy may be effective in the treatment of cervical cancer.C ervical cancer remains a major worldwide health concern. This is despite the use of Pap smears, a highly successful means for early detection of cervical cancer precursors but limited in its use to countries with highly developed health care systems. Current approaches for treating cancer have limited success; consequently, 5-year survival rates for women with cervical cancer remain low. It is estimated that 500,000 women annually will develop cervical cancer, and 200,000 women die every year from cervical cancer.Human papillomaviruses (HPVs) are associated with Ͼ99% of cervical cancers (1) and are considered to be the major etiologic factor in this and other anogenital cancers as well as a significant portion of head and neck cancers within the oral cavity (2). In HPV-associated cervical cancers, two HPV oncogenes, E6 and E7, are commonly up-regulated in their expression (3). E6 and E7, both multifunctional proteins, display transforming properties in tissue culture, including an ability to contribute to the immortalization process (4, 5). The in vivo properties of high-risk HPV E6 and E7 oncoproteins have been evaluated through the generation and characterization of HPV transgenic mouse strains (6-8). In these K14E6 and K14E7 mice, respectively, expression of the E6 and E7 genes of the high-risk HPV type 16 (HPV16) was directed to stratified epithelium, including the cervical epithelium, by the human kerati...

Performance of cytology and human papillomavirus testing in relation to the menstrual cycle

“…In both animal models and humans, oestrogen promotes epithelial hyperplasia, metaplasia, and maturation of cervical epithelium, creating a microenvironment suitable for HPV replication (Arbeit et al, 1996;Elson et al, 2000). In HPV 16 transgenic mice, estrogen treatment is required for carcinogenesis (Elson et al, 2000;Brake and Lambert, 2005). In cell cultures, oestrogen interacts with adhesion molecules, producing increased deformability and contraction, which theoretically could facilitate cellular exfoliation (Gorodeski, 1998).…”

All sites but skin cancer incidences analyzed worldwide by sex, age, and skin type over time (1955-2007), advancing age, and UVB dose reveals important carcinogenic drivers

“…[83] Estrogen is responsible for the onset, persistence, and malignant transformation of cervical cells [84] by stimulating oncogenic expression of HPV's E6 and E7 proteins promoting viral proliferation [17] and driving cells through the cell cycle. [85] Additionally, ROS activates HPV [16] and its E6 protein can in turn cause production of more ROS and DNA damage.…”

The role of Notch signaling in human cervical cancer: implications for solid tumors

“…This would perhaps be a promising approach to evaluate in the context of cervical cancers. A second approach would be to undertake an analysis of transgenic mice that express papillomavirus oncogenes (Brake and Lambert, 2005) and examine the role of Notch signaling in cervical cancers in situ. Finally, given the role of Notch ligands in regulating peripheral T-cell responses, an integration of cancer development with the immune system would complete the picture in terms of all the interactions.…”