title: Progression of mouse skin carcinogenesis is associated with increased ERα levels and is repressed by a dominant negative form of ERα.
abstract: Estrogen receptors (ER), namely ERα and ERβ, are hormone-activated transcription factors with an important role in carcinogenesis. In the present study, we aimed at elucidating the implication of ERα in skin cancer, using chemically-induced mouse skin tumours, as well as cell lines representing distinct stages of mouse skin oncogenesis. First, using immunohistochemical staining we showed that ERα is markedly increased in aggressive mouse skin tumours in vivo as compared to the papilloma tumours, whereas ERβ levels are low and become even lower in the aggressive spindle tumours of carcinogen-treated mice. Then, using the multistage mouse skin carcinogenesis model, we showed that ERα gradually increases during promotion and progression stages of mouse skin carcinogenesis, peaking at the most aggressive stage, whereas ERβ levels only slightly change throughout skin carcinogenesis. Stable transfection of the aggressive, spindle CarB cells with a dominant negative form of ERα (dnERα) resulted in reduced ERα levels and reduced binding to estrogen responsive elements (ERE)-containing sequences. We characterized two highly conserved EREs on the mouse ERα promoter through which dnERα decreased endogenous ERα levels. The dnERα-transfected CarB cells presented altered protein levels of cytoskeletal and cell adhesion molecules, slower growth rate and impaired anchorage-independent growth in vitro, whereas they gave smaller tumours with extended latency period of tumour onset in vivo. Our findings suggest an implication of ERα in the aggressiveness of spindle mouse skin cancer cells, possibly through regulation of genes affecting cell shape and adhesion, and they also provide hints for the effective targeting of spindle cancer cells by dnERα.
authors.affiliation: Biomedical Applications Unit, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
authors.forename: Stella
authors.initials: S
authors.lastname: Logotheti
authors.forename: Dimitra
authors.initials: D
authors.lastname: Papaevangeliou
authors.forename: Ioannis
authors.initials: I
authors.lastname: Michalopoulos
authors.forename: Maria
authors.initials: M
authors.lastname: Sideridou
authors.forename: Katerina
authors.initials: K
authors.lastname: Tsimaratou
authors.forename: Ioannis
authors.initials: I
authors.lastname: Christodoulou
authors.forename: Katerina
authors.initials: K
authors.lastname: Pyrillou
authors.forename: Vassilis
authors.initials: V
authors.lastname: Gorgoulis
authors.forename: Spiros
authors.initials: S
authors.lastname: Vlahopoulos
authors.forename: Vassilis
authors.initials: V
authors.lastname: Zoumpourlis
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology*; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005799:Genes, Dominant; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014162:Transfection
chemical_list: D002273:Carcinogens; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009363:Neoplasm Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene