Cervical cancer is one of the most common cancers in women and the second leading cause of death by cancer among women. Nearly half of all women who develop this cancer will die from it. Virtually all cervical cancers are caused by sexually transmitted, high-risk human papillomaviruses (HPVs), the most common of which is HPV16. In these cancers, two viral oncogenes are always expressed, E6 and E7 and are believed to be essential for these cancers to arise and persist. Understanding the mechanisms of action of E6 and E7 therefore could provide new insights into how to more effectively treat cervical cancer patients. We have developed HPV transgenic mouse strains in which to study how HPV16 E6 and E7 contribute to cervical cancer. By comparing the cancer incidence in mice expressing wild type or mutant forms of E6 and E7, and by crossing these mice to other genetically engineered mutant mouse strains, we can investigate the role of individual activities of E6 and E7, and the role of cellular genes and pathways in cervical cancer. During the past funding period we have learned that E6 and E7 cause cervical cancer through multiple activities, including but not limited to their inactivation of p53 and pRb, respectively. In this competitive renewal application, we will further define the mechanisms of action of E6 and E7 oncogenes in cervical cancer. We will also investigate the importance of the Notch signaling pathway, which has been directly implicated in cervical cancers.
Human papillomaviruses cause virtually all cervical cancers, the second leading cause of death by cancer among women, as well as other anogenital cancers and a subset of head and neck cancers. Approximately half of women who develop cervical cancer, die from it. By understanding how papillomaviruses cause cervical cancer we can define new means by which to treat more effectively cervical cancer patients and thereby improve their health and their life expectancy.
|Spurgeon, Megan E; Chung, Sang-Hyuk; Lambert, Paul F (2014) Recurrence of cervical cancer in mice after selective estrogen receptor modulator therapy. Am J Pathol 184:530-40|
|Park, J W; Shin, M-K; Lambert, P F (2014) High incidence of female reproductive tract cancers in FA-deficient HPV16-transgenic mice correlates with E7's induction of DNA damage response, an activity mediated by E7's inactivation of pocket proteins. Oncogene 33:3383-91|
|Park, Jung Wook; Shin, Myeong-Kyun; Pitot, Henry C et al. (2013) High incidence of HPV-associated head and neck cancers in FA deficient mice is associated with E7's induction of DNA damage through its inactivation of pocket proteins. PLoS One 8:e75056|
|Spurgeon, Megan E; Lambert, Paul F (2013) Merkel cell polyomavirus: a newly discovered human virus with oncogenic potential. Virology 435:118-30|
|Johannsen, Eric; Lambert, Paul F (2013) Epigenetics of human papillomaviruses. Virology 445:205-12|
|Yamben, Idella F; Rachel, Rivka A; Shatadal, Shalini et al. (2013) Scrib is required for epithelial cell identity and prevents epithelial to mesenchymal transition in the mouse. Dev Biol 384:41-52|
|Michael, Stella; Lambert, Paul F; Strati, Katerina (2013) The HPV16 oncogenes cause aberrant stem cell mobilization. Virology 443:218-25|
|Shin, Myeong-Kyun; Sage, Julien; Lambert, Paul F (2012) Inactivating all three rb family pocket proteins is insufficient to initiate cervical cancer. Cancer Res 72:5418-27|
|Bonilla-Delgado, José; Bulut, Gülay; Liu, Xuefeng et al. (2012) The E6 oncoprotein from HPV16 enhances the canonical Wnt/?-catenin pathway in skin epidermis in vivo. Mol Cancer Res 10:250-8|
|Ibarra Sierra, E; Diaz Chavez, J; Cortes-Malagon, E M et al. (2012) Differential gene expression between skin and cervix induced by the E7 oncoprotein in a transgenic mouse model. Virology 433:337-45|
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