| First Author | Logotheti S | Year | 2012 |
| Journal | PLoS One | Volume | 7 |
| Issue | 8 | Pages | e41957 |
| PubMed ID | 22870269 | Mgi Jnum | J:189663 |
| Mgi Id | MGI:5446827 | Doi | 10.1371/journal.pone.0041957 |
| Citation | Logotheti S, et al. (2012) Progression of mouse skin carcinogenesis is associated with increased ERalpha levels and is repressed by a dominant negative form of ERalpha. PLoS One 7(8):e41957 |
| abstractText | Estrogen receptors (ER), namely ERalpha and ERbeta, are hormone-activated transcription factors with an important role in carcinogenesis. In the present study, we aimed at elucidating the implication of ERalpha 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 ERalpha is markedly increased in aggressive mouse skin tumours in vivo as compared to the papilloma tumours, whereas ERbeta 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 ERalpha gradually increases during promotion and progression stages of mouse skin carcinogenesis, peaking at the most aggressive stage, whereas ERbeta levels only slightly change throughout skin carcinogenesis. Stable transfection of the aggressive, spindle CarB cells with a dominant negative form of ERalpha (dnERalpha) resulted in reduced ERalpha levels and reduced binding to estrogen responsive elements (ERE)-containing sequences. We characterized two highly conserved EREs on the mouse ERalpha promoter through which dnERalpha decreased endogenous ERalpha levels. The dnERalpha-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 ERalpha 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 dnERalpha. |
