Browsing by Author "Lambert, Paul F."
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Item Estrogen and ER?: Culprits in Cervical Cancer?(Trends in Endocrinology and Metabolism, 2010-08) Chung, Sang-Hyuk; Franceschi, Silvia; Lambert, Paul F.Estrogen and its receptors are implicated in the promotion and prevention of various cancers. While the uterine cervix is highly responsive to estrogen, the role of estrogen in cervical cancer, which is strongly associated with human papillomavirus (HPV) infections, is poorly understood. Recent studies in HPV transgenic mouse models provide evidence that estrogen and its nuclear receptor promote cervical cancer in combination with HPV oncogenes. While epidemiological studies further support this hypothesis, there is little experimental data assessing the hormonal responsiveness of human cervical cancers. If these cancers are dependent upon estrogen, then drugs targeting estrogen and its receptors may be effective in treating and/or preventing cervical cancer, the second leading cause of death by cancer amongst women worldwide.Item Prevention and treatment of cervical cancer in mice using estrogen receptor antagonists(Proceedings of the National Academy of Sciences, 11/17/2009) Chung, Sang-Hyuk; Lambert, Paul F.The majority of human cervical cancers are associated with the high-risk human papillomavirus (HPV) types. In mouse models for HPV-associated cancers, estrogen is required for the development of cervical and vaginal cancers. The estrogen receptor ? (ER?) also is required in mice for these cancers to arise. These data are consistent with the observation in women that long-term use of oral contraceptives or multiple pregnancies significantly increases the risk for cervical cancer in HPV-positive women. In the present study, we examined whether drugs that interfere with the function of ER? are effective in treating and/or preventing cervical cancer in mice. We provide evidence that a complete ER antagonist, ICI 182,780 (ICI), as well as a selective ER modulator, raloxifene, efficiently clear cancer and its precursor lesions in both the cervix and the vagina. Furthermore, ICI was capable of preventing the onset of cancers in mice bearing precursor lesions. These findings point to the potential value of ER antagonists in controlling gynecological disease in the lower reproductive tracts in women.Item Recurrence of Cervical Cancer in Mice after Selective Estrogen Receptor Modulator Therapy(American Journal of Pathology, 1/11/2014) Spurgeon, Megan E.; Chung, Sang-Hyuk; Lambert, Paul F.Estrogen and its nuclear receptor, estrogen receptor ?, 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 ? 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.Item Requirement for Estrogen Receptor ? in a Mouse Model for Human Papillomavirus–Associated Cervical Cancer(Cancer Research, 2009-12) Chung, Sang-Hyuk; Wiedmeyer, Kerri; Shai, Anny; Korach, Kenneth S.; Lambert, Paul F.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 ? (ER?) 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/ER??/? 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 ER?. We conclude that ER? plays a crucial role at an early stage of cervical carcinogenesis in this mouse model. [Cancer Res 2008;68(23):9928–34]Item Requirement for Stromal Estrogen Receptor Alpha in Cervical Neoplasia(Horomones and Cancer, 2/1/2014) Chung, Sang-Hyuk; Shin, Myeong Kyun; Korach, Kenneth S.; Lambert, Paul F.The major etiological factor for cervical cancer is the high-risk human papillomavirus (HPV), which encodes E6 and E7 oncogenes. However, HPV is not sufficient, and estrogen has been proposed as an etiological cofactor for the disease. Its requirement has been demonstrated in mouse models for HPV-associated cervical cancer (e.g., K14E7 transgenic mice). Although germline knockout of estrogen receptor alpha (ER?) renders mice resistant to cervical cancer, the cell-type-specific requirement for ER? is not known. In this study, we demonstrate that temporal deletion of stromal ER? induced complete regression of cervical dysplasia in K14E7mice. Our results strongly support the hypothesis that stromal ER? is necessary for HPV-induced cervical carcinogenesis and implicate paracrine mechanisms involving ER? signaling in the development of estrogen-dependent cervical cancers. This is the first evidence to support the importance of stromal ER? in estrogen-dependent neoplastic disease of the female reproductive tract.Item Requirement of estrogen receptor alpha DNA-binding domain for HPV oncogene-induced cervical carcinogenesis in mice(Carcinogenesis, 10/7/2013) Son, Jieun; Park, Jung Wook; Lambert, Paul F.; Chung, Sang-HyukCervical cancer is caused by human papillomavirus (HPV) in collaboration with other non-viral factors. The uterine cervix is hormone responsive and female hormones have been implicated in the pathogenesis of the disease. HPV transgenic mice expressing HPV16 oncogenes E6 ( K14E6 ) and/or E7 ( K14E7 ) have been employed to study a mechanism of estrogen and estrogen receptor ? (ER?) in cervical carcinogenesis. A chronic exposure to physiological levels of exogenous estrogen leads to cervical cancer in the HPV transgenic mice, which depends on ER?. The receptor is composed of multiple functional domains including a DNA-binding domain (DBD), which mediates its binding to estrogen-responsive elements (EREs) on target genes. A transcriptional control of genes by ER? is mediated by either DBD-dependent (classical) or DBD-independent (non-classical) pathway. Although molecular mechanisms of ER? in cancer have been characterized extensively, studies investigating importance of each pathway for carcinogenesis are scarce. In this study, we employ knock-in mice expressing an ER? DBD mutant (E207A/G208A) that is defective specifically for ERE binding. We demonstrate that the ER? DBD mutant fails to support estrogen-induced epithelial cell proliferation and carcinogenesis in the cervix of K14E7 transgenic mice. We also demonstrate that cervical diseases are absent in K14E7 mice when one ER? DBD mutant allele and one wild-type allele are present. We conclude that the ER? classical pathway is required for cervical carcinogenesis in a mouse model.Item The E6 Oncoprotein from HPV16 Enhances the Canonical Wnt/?-Catenin Pathway in Skin Epidermis In Vivo(Molecular Cancer Research, 2013-02) Bonilla-Delgado, José; Bulut, Gülay; Liu, Xuefeng; Cortés-Malagón, Enoc M.; Schlegel, Richard; Flores-Maldonado, Catalina; Contreras, Rubén G.; Chung, Sang-Hyuk; Lambert, Paul F.; Üren, Aykut; Gariglio,PatricioThe contribution of the Wnt signaling pathway to human papilloma virus (HPV)-induced carcinogenesis is poorly understood. In high-grade dysplastic lesions that are caused by high-risk HPVs (HR-HPV), ?-catenin is often located in the cell nucleus, which suggests that Wnt pathway may be involved in the development of HPV-related carcinomas. Most of the oncogenic potential of HR-HPVs resides on the PDZ-binding domain of E6 protein. We hypothesized that the PDZ-binding domain of the HPV16-E6 oncoprotein induces the nuclear accumulation of ?-catenin due to its capacity to degrade PDZ-containing cellular targets. To test this hypothesis, we evaluated the staining pattern of ?-catenin in the skin epidermis of transgenic mice expressing the full-length E6 oncoprotein (K14E6 mice) and measured LacZ gene expression in K14E6 mice that were crossed with a strain expressing LacZ that was knocked into the Axin2 locus (Axin2+/LacZ mice). Here, we show that the E6 oncoprotein enhances the nuclear accumulation of ?-catenin, the accumulation of cellular ?-catenin–responsive genes, and the expression of LacZ. None of these effects were observed when a truncated E6 oncoprotein that lacks the PDZ-binding domain was expressed alone (K14E6?PDZ mice) or in combination with Axin2+/LacZ. Conversely, cotransfection with either E6 or E6?PDZ similarly enhanced canonical Wnt signaling in short-term in vitro assays that used a luciferase Wnt/?-catenin/TCF-dependent promoter. We propose that the activation of canonical Wnt signaling could be induced by the HPV16-E6 oncoprotein; however, the participation of the E6 PDZ-binding domain seems to be important in in vivo models only. Mol Cancer Res; 10(2); 250–8. ©2011 AACR.