The role of cadmium and nickel in estrogen receptor signaling and breast cancer: metalloestrogens or not?

Abstract

During the past half-century, incidences of breast cancer have increased globally. Various factors--genetic and environmental--have been implicated in the initiation and progression of this disease. One potential environmental risk factor that has not received a lot of attention is the exposure to heavy metals. While several mechanisms have been put forth describing how high concentrations of heavy metals play a role in carcinogenesis, it is unclear whether chronic, low-level exposure to certain heavy metals (i.e., cadmium and nickel) can directly result in the development and progression of cancer. Cadmium and nickel have been hypothesized to play a role in breast cancer development by acting as metalloestrogens--metals that bind to estrogen receptors and mimic the actions of estrogen. Since the lifetime exposure to estrogen is a well-established risk factor for breast cancer, anything that mimics its activity will likely contribute to the etiology of the disease. However, heavy metals, depending on their concentration, are capable of binding to a variety of proteins and may exert their toxicities by disrupting multiple cellular functions, complicating the analysis of whether heavy metal-induced carcinogenesis is mediated by the estrogen receptor. The purpose of this review is to discuss the various epidemiological, in vivo, and in vitro studies that show a link between the heavy metals, cadmium and nickel, and breast cancer development. We will particularly focus on the studies that test whether these two metals act as metalloestrogens in order to assess the strength of the data supporting this hypothesis.

Figure 1. ERα and ERβ are homologous in their functional domains

The two ER isoforms display a high degree of homology in the DNA binding domain (DBD) and ligand binding domain (LBD), but are highly variable in the NH₂-terminal transactivation AF-1 domain, also referred to as the A/B hypervariable domain. Percentages indicate percent identity between the two receptors. Figure is adapted from the review by Gustafsson (179, 180).

Figure 2. Cross-talking between ERα/ERβ and GPR30 signaling pathways

Estrogen can activate both long-term genomic (left) and rapid nongenomic (right) pathways leading to the transcription of downstream genes necessary for cell growth and development. ERα/ERβ activation can lead to both direct transcription activation in the nucleus or via rapid signaling of mitogen-activated protein kinases (MAPKs). In contrast, GPR30 cannot directly activate transcription processes but can rapidily activate nongenomic signaling including the activation of MAPKs resulting in the expression of transcription factors such as c-fos. cAMP is also produced via GPR30 activation. ERα/ERβ nd GPR30 signaling can induce both positive and negative effects on one another, depending upon the signaling components in the cell at a given time. Several other regulatory pathways are possible but not shown. Figure adapted from Prossnitz 2008 (181). ERE, estrogen response element; SRE, serum response element; CRE, cAMP response element.