title: Critical role of estrogen receptor on anoikis and invasion of squamous cell carcinoma.
abstract: Estrogen receptor (ER) plays an important role in various physiological functions. We examined whether ERalpha and ERbeta are expressed in squamous cell carcinoma (SCC), and whether ER is a potential target for antitumor therapy. High-level expression of ERbeta, but not ERalpha, was observed in tumor cells of human primary SCC tissues and various SCC cultured cell lines. Treatment with ER antagonist (tamoxifen), but not agonist (estradiol), caused apoptotic cell death of SCC cells in a concentration- and time-dependent manner. Adhesion of SCC was inhibited by the treatment with tamoxifen, but not with estradiol. Tamoxifen reduced the phosphorylation of focal adhesion kinase (FAK), resulting in decreases in phosphorylation of extracellular signal-related kinase (Erk) and mitogen-activated protein kinase. Inhibition of FAK phosphorylation is accompanied by disorder of the cytoskeletal component actin. The cell death caused by tamoxifen is therefore the result of direct interference in cell adhesion, which is called 'anoikis', involving a decrease in intracellular FAK signaling. Expression of epidermal growth factor receptor was also inhibited by treatment with a high concentration of tamoxifen. Knockdown of ERbeta by small interfering RNA inhibited the proliferation of SCC. In addition, tamoxifen strongly inhibited invasion of SCC. These results imply a potentially important role for ER, whose inhibition may be effective for the treatment of SCC and the prevention of invasion and metastasis.
authors.affiliation: Department of Pharmacology, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishida
authors.forename: Koichiro
authors.initials: K
authors.lastname: Wada
authors.forename: Tomotake
authors.initials: T
authors.lastname: Masuda
authors.forename: Masaya
authors.initials: M
authors.lastname: Okura
authors.forename: Keiko
authors.initials: K
authors.lastname: Kohama
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Sano
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakajima
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Kogo
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kamisaki
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D023102:Anoikis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D034622:RNA Interference; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D013629:Tamoxifen; D004958:Estradiol; D011494:Protein Kinases