Requirement of ERα and basal activities of EGFR and Src kinase in Cd-induced activation of MAPK/ERK pathway in human breast cancer MCF-7 cells

Abstract

Cadmium (Cd) is a common environmental toxicant and an established carcinogen. Epidemiological studies implicate Cd with human breast cancer. Low micromolar concentrations of Cd promote proliferation of human breast cancer cells in vitro. The growth promotion of breast cancer cells is associated with the activation of MAPK/ERK pathway. This study explores the mechanism of Cd-induced activation of MAPK/ERK pathway. Specifically, the role of cell surface receptors ERα, EGFR, and Src kinase was evaluated in human breast cancer MCF-7 cells treated with 1–3 μM Cd. The activation of ERK was studied using a serum response element (SRE) luciferase reporter assay. Receptor phosphorylation was detected by Western blot analyses. Cd treatment increased both the SRE reporter activity and ERK1/2 phosphorylation in a concentration-dependent manner. Cd treatment had no effect on reactive oxygen species (ROS) generation. Also, blocking the entry of Cd into the cells with manganese did not diminish Cd-induced activation of MAPK/ERK. These results suggest that the effect of Cd was likely not caused by intracellular ROS generation, but through interaction with the membrane receptors. While Cd did not appear to activate either EGFR or Src kinase, their inhibition completely blocked the Cd-induced activation of ERK as well as cell proliferation. Similarly, silencing ERα with siRNA or use of ERα antagonist blocked the effects of Cd. Based on these results, it is concluded that not only ERα, but also basal activities of EGFR and Src kinase are essential for Cd-induced signal transduction and activation of MAPK/ERK pathway for breast cancer cell proliferation.

Anti-glycation and anti-oxidative effects of a phenolic-enriched maple syrup extract and its protective effects on normal human colon cells

“…As we previously reported, the cell proliferation assay was validated by using a known ERK inhibitor, namely, PD 184161. 44 We confirmed the cytotoxicity of MGO and AGE on the CCD-18Co cells by this assay where the untreated cells showed the highest viability (see Supplemental Information, Figure S2). In the pre-treatment groups, the cells were first challenged with 200 μM AGE for 12 h, then incubated with MSX for 48 h. As shown in Fig.…”

MiR-203 inhibits estrogen-induced viability, migration and invasion of estrogen receptor α-positive breast cancer cells

“…In addition, the functions of ERα, including chromatin interaction, co-regulator recruitment and gene expression, are regulated by phosphorylation through various kinase signaling pathways, such as mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphoinositide 3-kinase/protein kinase B, which have been found to be associated with breast cancer growth and metastasis (21,38,39). In the present study, it was found that miR-203 negatively mediated the protein expression of ERα via direct binding to the 3'UTR of its mRNA.…”

Periodic Mechanical Stress Activates PKCδ-Dependent EGFR Mitogenic Signals in Rat Chondrocytes via PI3K-Akt and ERK1/2

“…Despite the importance of EGFR in mediating chondrocyte proliferation, it is possible that other growth factor receptors may also play a role under conditions of mechanical stimuli. A number of autophosphorylation sites have been identified in the intracellular domain of EGFR, which allow for specific binding and activation of downstream signaling molecules [38,39]. The activation of ERK1/2 and PI3K by EGFR has recently been demonstrated to be a signaling transduction mechanism in SNU-407 colon cancer cells and MH1C1 cells [40,41].…”