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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA154358-01
Application #
7948898
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Blair, Donald G
Project Start
2010-07-01
Project End
2015-04-30
Budget Start
2010-07-01
Budget End
2011-04-30
Support Year
1
Fiscal Year
2010
Total Cost
$316,438
Indirect Cost
Name
Northwestern University at Chicago
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Cunha, Gerald R; Kurita, Takeshi; Cao, Mei et al. (2017) Response of xenografts of developing human female reproductive tracts to the synthetic estrogen, diethylstilbestrol. Differentiation 98:35-54
Robboy, Stanley J; Kurita, Takeshi; Baskin, Laurence et al. (2017) New insights into human female reproductive tract development. Differentiation 97:9-22
Wu, Xin; Serna, Vanida A; Thomas, Justin et al. (2017) Subtype-Specific Tumor-Associated Fibroblasts Contribute to the Pathogenesis of Uterine Leiomyoma. Cancer Res 77:6891-6901
Terakawa, Jumpei; Rocchi, Altea; Serna, Vanida A et al. (2016) FGFR2IIIb-MAPK Activity Is Required for Epithelial Cell Fate Decision in the Lower Müllerian Duct. Mol Endocrinol 30:783-95

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