During the last 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 or not these two metals act as metalloestrogens in order to assess the strength of the data supporting this hypothesis.

Cadmium is an omnipotent environmental contaminant associated with the development of breast cancer. Studies suggest that cadmium functions as an endocrine disruptor, mimicking the actions of estrogen in breast cancer cells and activating the receptor to promote cell growth. Although acute cadmium exposure is known to promote estrogen receptor-mediated gene expression associated with growth, the consequence of chronic cadmium exposure is unclear. Since heavy metals are known to bioaccumulate, it is necessary to understand the effects of prolonged cadmium exposure. This study aims to investigate the effects of chronic cadmium exposure on breast cancer progression. A MCF7 breast cancer cell line chronically exposed to 10−7 M CdCl2 serves as our model system. Data suggest that prolonged cadmium exposures result in the development of more aggressive cancer phenotypes – increased cell growth, migration and invasion. The results from this study show for the first time that chronic cadmium exposure stimulates the expression of SDF-1 by altering the molecular interactions between ERα, c-jun and c-fos. This study provides a mechanistic link between chronic cadmium exposure and ERα and demonstrates that prolonged, low-level cadmium exposure contributes to breast cancer progression.

Breast cancer is one of the most frequently diagnosed cancers among American women in the U.S. Studies suggest that environmental factors such as heavy metal exposure may contribute to development and progression of breast cancer. Cadmium has been shown to induce malignant transformation and increase the aggressive phenotype of mammary epithelial cells. The study focuses on understanding the effects of chronic cadmium exposure on breast cancer progression. Preliminary data show an increase in the ability of MCF‐7 cells to migrate and invade through the extracellular matrix with cadmium exposure. MCF‐7 cells chronically exposed to cadmium (MCF7‐CdC) express higher levels of SDF‐1, a protein associated with tumor invasion and metastasis. Additionally matrix metalloeproteinase‐9 (MMP‐9) activity was significantly higher in MCF7‐CdC cells. How SDF‐1 and MMP‐9 contribute to the aggressive phenotype of the cadmium exposed cells requires further research, and understanding their role in cadmium‐induced carcinogenesis will provide further insights to how heavy metals contribute to breast cancer progression.