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.

Increasing incidences of breast cancer have been a global public health concern, however the underlying cause remains unknown. Studies have suggested that exposure to elevated levels of heavy metals has been associated with deregulated cell growth and cell death. Heavy metals including nickel (Ni2+) are known to mimic the effects of estrogen and promote breast cancer cell growth, but its mechanism of action is unclear. To understand Ni2+ carcinogenicity, we examined the effects of Ni2+ on ER+ breast cancer cell (MCF‐7) growth. Our results suggest that acute and chronic Ni2+ exposure increases MCF‐7 cell growth. Further analysis at the molecular level indicate that the expression of several cell cycle genes were upregulated, whereas the expression of two cyclin‐dependent kinase inhibitors (CKI), p21 and p27 were significantly decreased in response to Ni2+ exposure. The ability of CKIs to induce cell cycle arrest is dependent upon their interaction with their respective cyclin/cyclin dependent kinase complex. Understanding the molecular mechanism of how nickel regulates the expression of CKIs, and the role of ERα in this process will provide insights to how Ni2+ contributes to breast cancer etiology.