The ultimate goal of this study is to elucidate the molecular mechanisms of cervical and vaginal adenosis development and its progression to adenocarcinoma. Cervical and vaginal adenosis is a congenital anomaly defined as the presence of columnar (tall) glandular cells in normally squamous (flat) epithelium of ectocervix and vagina. Cervical/vaginal adenosis has been studied in the context of cervical/vaginal clear cell adenocaricinoma (CCAC) associated with in utero exposure to a synthetic estrogen diethylstilbestrol (DES). Women exposed to DES in utero are at increased risk of developing CCAC, which is believed to arise from preexisting adenosis lesions. Although incidences have declined significantly after DES use for pregnant women was banned in 1971, cervical/vagina adenosis and CCAC are still reported in women without history of DES exposure, suggesting that there are other factors that contribute to these conditions in the environment. Using a mouse model, we have previously demonstrated that developmental exposure to DES induces cervical/vaginal adenosis by disrupting expression of p63 transcription factor, which is essential for development of squamous epithelia. To elucidate the pathogenesis of cervical/vaginal adenosis, we propose to study signaling mechanism that induces p63 expression in developing cervical/vaginal epithelium, and how developmental exposure to estrogen and thyroid hormone disrupts this signaling. Primarily, we will study how p63 promoter is developmentally regulated using mouse model and reporter assay system with cell line. In addition, we also propose to study progression of adenosis to adenocarcinoma. The cervical and vaginal CCACs are generally negative for human papilloma virus (HPV) infection, and their etiology is not understood. Recently, high incidence of mutations in PIK3Ca or PTEN gene resulting in uncontrolled-activation of PI3K (phosphatidylinositol-3 kinase) signaling has been reported in CCACs of cervix. Therefore, we will explore whether uncontrolled-activation of PI3K signaling transforms adenosis into adenocarcinoma using double knockout mouse model for p63 and Pten tumor suppressor. The knowledge obtained from this study will help us identify potential risk factors that exist in our environment for cervical/vaginal adenosis. In addition, by studying molecular etiology of HPV-negative cervical/vaginal adenocarcinoma, it may lead to early detection and discovery of a new and improved treatment for this disease.
Although adenocarcinomas of ectocervix and vagina are believed to arise from preexisting benign adenosis lesions, its etiology is unknown. This project will identify the risk factor (e.g. environmental chemicals) for adenosis and adenocarcinoma of ectocervix and vagina by elucidating the molecular pathogenesis of these conditions.
|Qiang, Wenan; Liu, Zhaojian; Serna, Vanida Ann et al. (2014) Down-regulation of miR-29b is essential for pathogenesis of uterine leiomyoma. Endocrinology 155:663-9|
|Bertsch, Elizabeth; Qiang, Wenan; Zhang, Qing et al. (2014) MED12 and HMGA2 mutations: two independent genetic events in uterine leiomyoma and leiomyosarcoma. Mod Pathol 27:1144-53|
|Xu, Xiaofei; Ayub, Bushra; Liu, Zhaojian et al. (2014) Anti-miR182 reduces ovarian cancer burden, invasion, and metastasis: an in vivo study in orthotopic xenografts of nude mice. Mol Cancer Ther 13:1729-39|
|Sefton, Elizabeth C; Qiang, Wenan; Serna, Vanida et al. (2013) MK-2206, an AKT inhibitor, promotes caspase-independent cell death and inhibits leiomyoma growth. Endocrinology 154:4046-57|
|Laronda, Monica M; Unno, Kenji; Ishi, Kazutomo et al. (2013) Diethylstilbestrol induces vaginal adenosis by disrupting SMAD/RUNX1-mediated cell fate decision in the Mullerian duct epithelium. Dev Biol 381:5-16|
|Kim, J Julie; Kurita, Takeshi; Bulun, Serdar E (2013) Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer. Endocr Rev 34:130-62|
|Romano, Rose-Anne; Smalley, Kirsten; Magraw, Caitlin et al. (2012) ýýNp63 knockout mice reveal its indispensable role as a master regulator of epithelial development and differentiation. Development 139:772-82|
|Kurita, Takeshi (2011) Normal and abnormal epithelial differentiation in the female reproductive tract. Differentiation 82:117-26|
|Murashima, Aki; Miyagawa, Shinichi; Ogino, Yukiko et al. (2011) Essential roles of androgen signaling in Wolffian duct stabilization and epididymal cell differentiation. Endocrinology 152:1640-51|
|Memarzadeh, Sanaz; Zong, Yang; Janzen, Deanna M et al. (2010) Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium. Proc Natl Acad Sci U S A 107:17298-303|
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