title: Recurrence of cervical cancer in mice after selective estrogen receptor modulator therapy.
abstract: Estrogen and its nuclear receptor, estrogen receptor α, are necessary cofactors in the initiation and multistage progression of carcinogenesis in the K14E6/E7 transgenic mouse model of human papillomavirus-associated cervical cancer. Recently, our laboratory reported that raloxifene, a selective estrogen receptor modulator, promoted regression of high-grade dysplasia and cancer that arose in the cervix of K14E6/E7 transgenic mice treated long-term with estrogen. Herein, we evaluated the recurrence of cervical cancer after raloxifene therapy in our preclinical model of human papillomavirus-associated cervical carcinogenesis. We observed recurrence of cervical cancer in mice re-exposed to estrogen after raloxifene treatment, despite evidence suggesting the antagonistic effects of raloxifene persisted in the reproductive tract after treatment had ceased. We also observed recurrence of neoplastic disease in mice that were not retreated with exogenous estrogen, although the severity of disease was less. Recurrent neoplastic disease and cancers retained functional estrogen receptor α and responded to retreatment with raloxifene. Moreover, continuous treatment of mice with raloxifene prevented the emergence of recurrent disease seen in mice in which raloxifene was discontinued. These data suggest that cervical cancer cells are not completely eradicated by raloxifene and rapidly expand if raloxifene treatment is ceased. These findings indicate that a prolonged treatment period with raloxifene might be required to prevent recurrence of neoplastic disease and lower reproductive tract cancers.
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Spurgeon
authors.affiliation: Department of Biology and Biochemistry, the Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, Texas.
authors.forename: Sang-Hyuk
authors.initials: SH
authors.lastname: Chung
authors.affiliation: Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. Electronic address: plambert@wisc.edu.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Lambert
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005836:Genitalia, Female / Q000187:drug effects / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology*; D011379:Prognosis; D020849:Raloxifene Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D004967:Estrogens; D020845:Selective Estrogen Receptor Modulators; D020849:Raloxifene Hydrochloride