Cadmium induces mitogenic signaling in breast cancer cell by an ERalpha-dependent mechanism.
Breast cancer (BC) is linked to estrogen exposure. Estradiol (E2) stimulates BC cells proliferation by binding the estrogen receptor (ER). Hormone-related cancers have been linked to estrogenic environmental contaminants. Cadmium (Cd) a toxic pollutant, acts as estrogens in BC cells. Purpose of our study was to evaluate whether Cd regulates MCF-7 cell proliferation by activating ERK1/2, Akt and PDGFRalpha kinases. Cd increased cell proliferation and the ER-antagonist ICI 182,780 blunted it. To characterize an ER-dependent mechanism, ERalpha/beta expression was evaluated. Cd decreased ERalpha expression, but not ERbeta. Cd also increased ERK1/2, Akt and PDGFRalpha phosphorylation while ICI blocked it. Since stimulation of phosphorylation was slower than expected, c-fos and c-jun proto-oncogenes, and PDGFA were analyzed. Cd rapidly increased c-jun, c-fos and PDGFA expression. Cells were also co-incubated with the Cd and specific kinases inhibitors, which blocked the Cd-stimulated proliferation. In conclusion, our results indicate that Cd increases BC cell proliferation in vitro by stimulating Akt, ERK1/2 and PDGFRalpha kinases activity likely by activating c-fos, c-jun and PDGFA by an ERalpha-dependent mechanism.
Brama
Marina
M
Department of Biochemical Sciences, University La Sapienza, P.le A.Moro 5, 00185 Roma, Italy.
Gnessi
Lucio
L
Basciani
Sabrina
S
Cerulli
Nicola
N
Politi
Laura
L
Spera
Giovanni
G
Mariani
Stefania
S
Cherubini
Sara
S
Scotto d'Abusco
Anna
A
Scandurra
Roberto
R
Migliaccio
Silvia
S
D001943:Breast Neoplasms / Q000378:metabolism*; D002104:Cadmium / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004785:Environmental Pollutants / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D011494:Protein Kinases / Q000096:biosynthesis; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D004785:Environmental Pollutants; D047628:Estrogen Receptor alpha; D004967:Estrogens; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D002104:Cadmium; D011494:Protein Kinases