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