Abstract
Cadmium is an environmental contaminant that can activate estrogen receptor alpha (ERα) and contribute to the development and progression of breast cancer. Our lab previously demonstrated that chronic cadmium exposure alters the expression of several ERα-responsive genes and increases the malignancy of breast cancer cells. Although these studies support cadmium’s function as a hormone disrupter, the role of ERα in cadmium-induced breast cancer progression remains unclear. To address this, we modulated the expression of ERα and found that while the loss of ERα significantly impaired cancer cell growth, migration, invasion and anchorage-independent growth in both MCF7 and MCF7-Cd cells, cadmium-exposed cells retained a significant advantage in cell growth, migration, and invasion, and partially circumvented the loss of ERα. ERα knockout in MCF7 and MCF7-Cd cells significantly reduced the expression of classical ERα-regulated genes, while non-classical ERα-regulated genes were less impacted by the loss of ERα in MCF7-Cd cells. This is the first study to show that chronic cadmium exposure, even at low levels, can increase the malignancy of breast cancer cells by decreasing their dependency on ERα and increasing the adaptability of the cancer cells.
Highlights
Breast cancer is the most common malignancy affecting women in the United States
There is evidence suggesting that cadmium functions as a metalloestrogen, it is unclear whether this mechanism directly contributes to the development and progression of breast cancer
To investigate how the loss of ERα affects the phenotypes of MCF7 and cadmium-adapted cells (MCF7-Cd), we measured the doubling times for all the clones lacking ERα (ΔERα) compared to those of the control cells by determining the total cell number at day 0, 2, 3, and 4
Summary
Breast cancer is the most common malignancy affecting women in the United States. Approximately 60–70% of breast cancers express estrogen receptor-alpha (ERα), and life-time exposure to estrogens, including those from the environment, is known to contribute to the development of breast cancer[1,2]. A study comparing cadmium concentrations in tissue, blood, and urine of malignant and benign breast cancer patients showed that cadmium levels were significantly higher in patients with malignant tumors than those with benign tumors and that ERα-positive breast cancers had significantly higher cadmium concentrations than ERα-negative cancers[5] These correlations suggest that cadmium might be a critical factor in tumors expressing ERα. Our lab found that MCF7 cells exposed to low levels of cadmium for six months had a unique gene expression profile and increased growth, migration, and invasion capabilities, indicating that chronic cadmium exposure promotes breast cancer progression[16,17] by altering the interactions among ERα, c-jun, and c-fos[16] and promoting the expression of SDF1, a chemokine regulated by ERα18,19. Our results demonstrate that ERα plays an important role in cadmium-induced gene expression and mediates malignant phenotypes, chronic cadmium exposure decreases the dependency of MCF7 cells on ERα
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