Requirement for estrogen receptor alpha in a mouse model for human papillomavirus-associated cervical cancer.
The majority of human cervical cancers are associated with the high-risk human papillomaviruses (HPV), which encode the potent E6 and E7 oncogenes. On prolonged treatment with physiologic levels of exogenous estrogen, K14E7 transgenic mice expressing HPV-16 E7 oncoprotein in their squamous epithelia succumb to uterine cervical cancer. Furthermore, prolonged withdrawal of exogenous estrogen results in complete or partial regression of tumors in this mouse model. In the current study, we investigated whether estrogen receptor alpha (ERalpha) is required for the development of cervical cancer in K14E7 transgenic mice. We show that exogenous estrogen fails to promote either dysplasia or cervical cancer in K14E7/ERalpha-/- mice despite the continued presence of the presumed cervical cancer precursor cell type, reserve cells, and evidence for E7 expression therein. We also observed that cervical cancers in our mouse models are strictly associated with atypical squamous metaplasia (ASM), which is believed to be the precursor for cervical cancer in women. Consistently, E7 and exogenous estrogen failed to promote ASM in the absence of ERalpha. We conclude that ERalpha plays a crucial role at an early stage of cervical carcinogenesis in this mouse model.
Chung
Sang-Hyuk
SH
McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA.
Wiedmeyer
Kerri
K
Shai
Anny
A
Korach
Kenneth S
KS
Lambert
Paul F
PF
D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D048708:Cell Growth Processes / Q000502:physiology; D002472:Cell Transformation, Viral / Q000502:physiology*; D002584:Cervix Uteri / Q000473:pathology / Q000821:virology; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D052162:Human papillomavirus 16 / Q000235:genetics / Q000254:growth & development*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D064168:Minichromosome Maintenance Complex Component 7; D009687:Nuclear Proteins / Q000096:biosynthesis; D009856:Oncogene Proteins, Viral / Q000235:genetics; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; C491086:Mcm7 protein, mouse; D064168:Minichromosome Maintenance Complex Component 7