Expression of Ezrin and Estrogen Receptors During Cervical Carcinogenesis.
Development of cervical squamous carcinoma (CXCA) is accompanied by changes in estrogen receptors (ERs, ERα and ERβ) and ezrin expression; however, reports have been conflicting. Using histologically documented staging of cervical biopsies, we determined ezrin and ER relationships during CXCA development.



Immunoreactive (ir) ezrin, ir-ERα, and ir-ERβ were studied in normal epithelium, carcinoma in situ/cervical intraepithelial neoplasia (CIN) 1 to 3, and local invasion or metastatic CXCA. Results were compared using H scoring. Cultures of Caski metastatic CXCA cells were treated with estradiol and/or tamoxifen and studied for ER-driven ir-ezrin and the morphologic response.



Koilocytosis was present and indicated viral presence. The ezrin H score increased from CIN1 to CIN3, reaching significant differences from normal by CIN3 ( P = .004) and 2× normal in metastatic CXCA. Estrogen receptor α and ERβ H scores fell, reaching significance by CIN3 (ERα, P = .0001; ERβ, P = .024). During estradiol treatment, ezrin in Caski cells increased and localized to the periphery, in ruffles and processes. The selective ER modulator tamoxifen blocked the estradiol-induced changes.



During cervical carcinogenesis, the usual relationship between estrogen and ezrin induction is abridged. This is consistent with the effects of human papilloma virus viral proteins such as E6 and E7 that upregulate SIX1, a protein that induces ezrin. Cervical carcinogenesis is progressive but arrests at the preinvasive stage for varying lengths of time. These studies suggest that changes in ezrin may be associated with the development of the invasive phenotype and penetration of the basement membrane. They also raise the possibility that inhibiting ezrin expression could be a target for the prevention of invasive CXCA.
1 Department of Obstetrics and Gynecology, New York University Langone Medical Center, New York, NY, USA.
Ahmed
A
Fadiel
1 Department of Obstetrics and Gynecology, New York University Langone Medical Center, New York, NY, USA.|2 Department of Obstetrics and Gynecology, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea.
Seung Do
SD
Choi
3 Department of Obstetrics and Gynecology, Soonchunhyang University College of Medicine, Seoul, Republic of Korea.
Bora
B
Park
4 Department of Obstetrics and Gynecology, Soonchunhyang University College of Medicine, Bucheon, Republic of Korea.
Tae-Hee
TH
Kim
1 Department of Obstetrics and Gynecology, New York University Langone Medical Center, New York, NY, USA.
Julia
J
Buldo-Licciardi
1 Department of Obstetrics and Gynecology, New York University Langone Medical Center, New York, NY, USA.
Mitra
M
Ahmadi
1 Department of Obstetrics and Gynecology, New York University Langone Medical Center, New York, NY, USA.
Alan
A
Arslan
1 Department of Obstetrics and Gynecology, New York University Langone Medical Center, New York, NY, USA.
Khushbakhat
K
Mittal
1 Department of Obstetrics and Gynecology, New York University Langone Medical Center, New York, NY, USA.
Frederick
F
Naftolin
D003598:Cytoskeletal Proteins / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism*; D004967:Estrogens / Q000008:administration & dosage; D005260:Female; D006801:Humans; D030361:Papillomavirus Infections / Q000378:metabolism; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D000099149:Ezrin
D003598:Cytoskeletal Proteins; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D000099149:Ezrin; C506487:ESR1 protein, human
carcinogenesis; cervical cancer; estradiol; ezrin