Progression of mouse skin carcinogenesis is associated with increased ER? levels and is repressed by a dominant negative form of ER?.

ABSTRACT: Estrogen receptors (ER), namely ER? and ER?, are hormone-activated transcription factors with an important role in carcinogenesis. In the present study, we aimed at elucidating the implication of ER? 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 ER? is markedly increased in aggressive mouse skin tumours in vivo as compared to the papilloma tumours, whereas ER? 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 ER? gradually increases during promotion and progression stages of mouse skin carcinogenesis, peaking at the most aggressive stage, whereas ER? levels only slightly change throughout skin carcinogenesis. Stable transfection of the aggressive, spindle CarB cells with a dominant negative form of ER? (dnER?) resulted in reduced ER? levels and reduced binding to estrogen responsive elements (ERE)-containing sequences. We characterized two highly conserved EREs on the mouse ER? promoter through which dnER? decreased endogenous ER? levels. The dnER?-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 ER? 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 dnER?.

SUBMITTER: Logotheti S 

PROVIDER: S-EPMC3411716 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature