Effects of cadmium on estrogen receptor mediated signaling and estrogen induced DNA synthesis in T47D human breast cancer cells

• Published in: Toxicology letters Vol. 184; no. 2; pp. 134 - 138
• Main Authors: Zang, Yu, Odwin-DaCosta, Shelly, Yager, James D.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 30.01.2009; Elsevier
• Subjects: Biological and medical sciences; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cadmium; Cadmium Chloride - toxicity; Carcinogens, Environmental - toxicity; Cell Line, Tumor; Chemical and industrial products toxicology. Toxic occupational diseases; DNA synthesis; DNA, Neoplasm - biosynthesis; Dose-Response Relationship, Drug; Drug Synergism; Estradiol - pharmacology; Estrogen receptor signaling; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; Medical sciences; Metals and various inorganic compounds; Phosphorylation; Receptors, Estrogen - metabolism; Receptors, Progesterone - metabolism; Signal Transduction; T47D cells; Toxicology; Tumors; Cadmium; DNA synthesis; T47D cells; Estrogen receptor signaling; Human; Estrogen receptor; Breast disease; Estrogen; Transition metal; Breast cancer; Malignant tumor; Ovarian hormone; Heavy metal; Mammary gland diseases; Signaling pathway; Sex steroid hormone; Tumor cell; Cancer; Hormonal receptor
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2008.10.032

Cadmium (Cd) has been shown to bind to the human estrogen receptor (ER), yet studies on Cd's estrogenic effects have yielded inconsistent results. In this study, we investigated the effects of Cd on DNA synthesis and its simultaneous effects on both genomic (mediated by nuclear ER (nER)) and non-genomic (mediated by membrane-bound ER (mER)) signaling in human breast cancer derived T47D cells. No effects on DNA synthesis were observed for non-cytotoxic concentrations of CdCl 2 (0.1–1000 nM), and Cd did not increase progesterone receptor (PgR) or pS2 mRNA levels. However, Cd stimulated phosphorylation of ERK1/2 MAPK, detectable following 10 min and 18 h of treatment. The sustained Cd-induced ERK1/2 phosphorylation was inhibited by the ER antagonist ICI 182,780, suggesting the involvement of ER. In addition, Cd enhanced DNA synthesis and pS2 mRNA levels in estrogen (10 pM estradiol) treated T47D cells. The MEK1/2 specific inhibitor U0126 blocked DNA synthesis stimulated by estradiol (E2) and the E2–Cd mixtures. These findings indicate that the ERK1/2 signaling is critical in E2-related DNA synthesis. The sustained ERK1/2 phosphorylation may contribute to the Cd-induced enhancement of DNA synthesis and pS2 mRNA in mixture with low-concentration E2.