title: Estrogen and cytochrome P450 1B1 contribute to both early- and late-stage head and neck carcinogenesis.
abstract: Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most common type of cancer in the United States. The goal of this study was to evaluate the contribution of estrogens to the development of HNSCCs. Various cell lines derived from early- and late-stage head and neck lesions were used to characterize the expression of estrogen synthesis and metabolism genes, including cytochrome P450 (CYP) 1B1, examine the effect of estrogen on gene expression, and evaluate the role of CYP1B1 and/or estrogen in cell motility, proliferation, and apoptosis. Estrogen metabolism genes (CYP1B1, CYP1A1, catechol-o-methyltransferase, UDP-glucuronosyltransferase 1A1, and glutathione-S-transferase P1) and estrogen receptor (ER) β were expressed in cell lines derived from both premalignant (MSK-Leuk1) and malignant (HNSCC) lesions. Exposure to estrogen induced CYP1B1 2.3- to 3.6-fold relative to vehicle-treated controls (P = 0.0004) in MSK-Leuk1 cells but not in HNSCC cells. CYP1B1 knockdown by shRNA reduced the migration and proliferation of MSK-Leuk1 cells by 57% and 45%, respectively. Exposure of MSK-Leuk1 cells to estrogen inhibited apoptosis by 26%, whereas supplementation with the antiestrogen fulvestrant restored estrogen-dependent apoptosis. Representation of the estrogen pathway in human head and neck tissues from 128 patients was examined using tissue microarrays. The majority of the samples exhibited immunohistochemical staining for ERβ (91.9%), CYP1B1 (99.4%), and 17β-estradiol (88.4%). CYP1B1 and ERβ were elevated in HNSCCs relative to normal epithelium (P = 0.024 and 0.008, respectively). These data provide novel insight into the mechanisms underlying head and neck carcinogenesis and facilitate the identification of new targets for chemopreventive intervention.
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
authors.forename: Ekaterina G
authors.initials: EG
authors.lastname: Shatalova
authors.forename: Andres J P
authors.initials: AJ
authors.lastname: Klein-Szanto
authors.forename: Karthik
authors.initials: K
authors.lastname: Devarajan
authors.forename: Edna
authors.initials: E
authors.lastname: Cukierman
authors.forename: Margie L
authors.initials: ML
authors.lastname: Clapper
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D065633:Cytochrome P-450 CYP1B1; D004958:Estradiol / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D007971:Leukoplakia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured
chemical_list: D047629:Estrogen Receptor beta; D004967:Estrogens; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D004958:Estradiol; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1