Molecular and Cellular Endocrinology 264 (2007) 102–108 Cadmium induces mitogenic signaling in breast cancer cell by an ER-dependent mechanism Marina Brama a,b , Lucio Gnessi b , Sabrina Basciani b , Nicola Cerulli c , Laura Politi a , Giovanni Spera b , Stefania Mariani b , Sara Cherubini b , Anna Scotto d’Abusco a , Roberto Scandurra a,1 , Silvia Migliaccio b,∗,1 a Department of Biochemical Sciences, University “La Sapienza”, P.le A.Moro 5, 00185 Roma, Itlay b Departments of Medical Physiopathology, Universit` a “La Sapienza”, Policlinico Umberto I, Viale del Policlinico 155, 00161 Roma, Italy c Department of Urology, University “La Sapienza”, Policlinico Umberto I, Viale del Policlinico 155, 00161 Roma, Italy Received 17 March 2006; received in revised form 12 October 2006; accepted 13 October 2006 Abstract Breast cancer (BC) is linked to estrogen exposure. Estradiol (E 2 ) 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 PDGFR kinases. Cd increased cell proliferation and the ER-antagonist ICI 182,780 blunted it. To characterize an ER-dependent mechanism, ER/ expression was evaluated. Cd decreased ER expression, but not ER. Cd also increased ERK1/2, Akt and PDGFR 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 PDGFR kinases activity likely by activating c-fos, c-jun and PDGFA by an ER-dependent mechanism. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Cadmium; Estrogen receptor; Estradiol; Breast cancer; MAPKs; Akt; PDGFR; Proto-oncogens 1. Introduction Breast cancer (BC) is the most common malignancy affecting women and is the leading cause of death in women between the ages of 35 and 45 years (Stoica et al., 2000) despite improve- ments in both cancer prevention and pharmacological treat- ments. BC develops through multistep processes progressing from hyperplasia to premalignant lesions, in situ carcinoma, invasion, and distal metastasis, concomitantly with gain of onco- genic activities and loss of tumor suppressor gene functions (Russo and Russo, 2001). Long-term exposure to estrogens has been linked to increased cell proliferation and thus, to both breast and uterine cancer (Clemons and Goss, 2001). Indeed the growth ∗ Corresponding author. Tel.: +39 0649970721; fax: +39 064461450. E-mail address: silvia.migliaccio@uniroma1.it (S. Migliaccio). 1 Both author contributed equally. and development of the mammary gland is under the control of sex steroids and the increased proliferation of normal cells induced long term exposure to estrogens has been suggested to be a strong stimulus for tumors promotion in these organs (Yager, 2000). However, the factors involved in the increased BC risk are not fully known. Interestingly, several studies suggest that expo- sure to pollutants and environmental endocrine disruptors might play a role in the aetiology of the disease (Lemen et al., 1976; McLachlan, 2001a,b), and also the high incidence of hormone- related cancers and diseases in the Western world has been related to environmental estrogens, able to bind and activate ERs in target tissues (McLachlan, 2001a,b; Migliaccio and Anderson, 2003). Estrogenic actions are mediated by two specific intracel- lular estrogen receptors, ER and ER, which belong to the steroid/thyroid hormone superfamily of transcription factors (Enmark and Gustafsson, 1999; Migliaccio and Anderson, 0303-7207/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2006.10.013