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Chronic cadmium exposure stimulates SDF-1 expression in an ERα dependent manner.

ABSTRACT: 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.

SUBMITTER: Ponce E

PROVIDER: S-EPMC3755996 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Chronic cadmium exposure decreases the dependency of MCF7 breast cancer cells on ERα.

Project description: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.

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Chronic cadmium exposure decreases the dependency of MCF7 breast cancer cells on ERα

Project description:To understand how chronic cadmium exposure alters the dependency of ERα in terms of gene expression, we transiently silenced ERα using ICI, an antiestrogen that promotes the degradation of ERα. MCF7 and cadmium-adapted cells (Cd7 and Cd12) were treated with ICI to mediate the degradation of ERα, and a nonbiased global gene expression analysis was conducted using RNA-seq. MCF7 shared 67.3% and 59.5% of the DE genes with Cd7 and Cd12 cells, respectively, suggesting that ERα continues to play an important role in regulating the expression of genes following chronic cadmium exposure. 138 ERE genes (76.7%) were shared by all three cell lines, in that expression changed in the same direction (either up- or downregulated). For the estrogen-responsive genes, 428 (53.6%) of the 799 genes were altered in the same direction in all three cell lines. These findings show that while a majority of ERE genes responded in the same manner to loss of ERα, more variability existed within the estrogen-responsive genes. Collectively, these results indicate that while chronic cadmium exposure leads to genome-wide transcriptional changes, ERα remains important for regulating the expression of genes and maintaining the malignant phenotypes associated with breast cancer progression.

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SDF-1alpha stimulates JNK3 activity via eNOS-dependent nitrosylation of MKP7 to enhance endothelial migration.

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The effects of chronic cadmium exposure on gene expression in MCF7 breast cancer cells

Project description:Cadmium is a metalloestrogen known to activate the estrogen receptor and promote breast cancer cell growth. Previous studies have implicated cadmium in the development of more malignant tumors; however the molecular mechanisms behind this cadmium-induced malignancy remain elusive. Using clonal cell lines derived by exposing breast cancer cells to cadmium for over 6 month (MCF7-Cd4, -Cd6, -Cd7, -Cd8 and -Cd12), this study aims to identify gene expression signatures associated with chronic cadmium exposure. Our results demonstrate that prolonged exposure does not merely result in the deregulation of genes but actually leads to a distinctive expression profile. The genes deregulated in cadmium-exposed cells are involved in multiple biological processes (i.e cell growth, apoptosis, etc.) and molecular functions (i.e. cadmium/metal ion binding, transcription factor activity, etc). Hierarchical clustering demonstrates that the five clonal cadmium cell lines share a common gene expression signature of breast cancer associated genes, clearly differentiating control from cadmium exposed cells. The results presented in this study offer insights into the cellular and molecular impacts of cadmium on breast cancer carcinogenesis and emphasize the importance of studying chronic cadmium exposure as one possible mechanism of promoting breast cancer progression. To understand the effects of chronic cadmium exposure on gene expression in breast cancer, two control MCF7 parental cell lines and five different clonal cadmium-adapted cell lines (MCF7-Cd4, -Cd6, -Cd7, -Cd8, and -Cd12) - previously derived from cells chronically exposed to cadmium - were used for microarray analysis.

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Chronic cadmium exposure decreases the dependency of MCF7 breast cancer cells on ERα

Project description:Chronic cadmium exposure decreases the dependency of MCF7 breast cancer cells on ERα

| PRJNA554005 | ENA

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2021-01-25 | GSE158455 | GEO

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