Interactions between cadmium and 17β-estradiol at physiologically relevant levels evoke unsynchronized events in MCF-7 breast cancer cells: Impaired cell growth and activation of estrogen receptor α-related pathways

Cadmium (Cd), a heavy metal, is implicated in the development of estrogen receptor α (ERα)-positive breast cancers (BCs). However, controversy surrounds whether Cd is estrogenic or anti-estrogenic for the malignancy of in vivo animal models and human observational/epidemiological studies, a debate also presents in in vitro experiments. The development of ERα-positive BCs is stimulated by circulating 17β-estradiol (E2). Thus, potential biological interactions between E2 and Cd in the progression of ERα-positive BCs exist. Although the interactions between Cd and E2 at physiologically relevant levels (1 nM each) may not have been confirmed in vitro, it is likely to occur. Therefore, this study aims to investigate the interactions of chemicals in human BC MCF-7 cells (ERα-positive) using a sequential exposure system in which chemicals are added to cells every 24–48 h. Pretreatment with Cd, but not secondary treatment, interfered with E2-mediated oncogenic actions by inducing cell cycle arrest at the S phase. This was accompanied by changes in the expression of genes regulating the cell cycle checkpoint and upregulation of the tumor suppressor metallothionein 1F gene, which E2 suppressed. Paradoxically, ERα-mediated estrogenic pathways were upregulated. In conclusion, this study is the first to show that physiologically relevant levels of Cd may dampen E2-induced oncogenic events independent of the E2/ERα-mediated pathway.