Abstract
Despite significant advances in early detection and treatment, breast cancer remains a major cause of morbidity and mortality. Perfluorooctanoic acid (PFOA) is a suspected endocrine disruptor and a common environmental pollutant associated with various diseases including cancer. However, the effects of PFOA and its mechanisms of action on hormone-responsive cells remain unclear. Here, we explored the potential tumorigenic activity of PFOA (100 nM–1 mM) in human breast epithelial cells (MCF-10A). MCF-10A cells exposed to 50 and 100 µM PFOA demonstrated a higher growth rate compared to controls. The compound promoted MCF-10A proliferation by accelerating G0/G1 to S phase transition of the cell cycle. PFOA increased cyclin D1 and CDK4/6 levels, concomitant with a decrease in p27. In contrast to previous studies of perfluorooctane sulfate (PFOS), the estrogen receptor antagonist ICI 182,780 had no effect on PFOA-induced cell proliferation, whereas the PPARα antagonist GW 6471 was able to prevent the MCF-10A proliferation, indicating that the underlying mechanisms involve PPARα-dependent pathways. Interestingly, we also showed that PFOA is able to stimulate cell migration and invasion, demonstrating its potential to induce neoplastic transformation of human breast epithelial cells. These results suggest that more attention should be paid to the roles of PFOA in the development and progression of breast cancer.
Highlights
Breast cancer is one of the most common malignancies that women in Western countries may develop in their lifetime (Gullick et al 1998)
Since we found an increase in cell proliferation of cells treated with 50–100 μM Perfluorooctanoic acid (PFOA), we determined the effects of PFOA exposure on cell cycle distribution using propidium iodide (PI) staining and flow cytometry analysis
The fluorescence microscopy images revealed a reduced p27 level (Fig. 2a, b) and increased CDK6 (Fig. 2a, c), CDK4 and cyclin D levels (Fig. 2d–m), with no alteration on p21 and p53 levels (Fig. 2g–o). Confirming these results, flow cytometry analysis showed a decrease in the mean fluorescence intensity in p27-staining (Fig. 2j), and an increase in the fluorescence intensity in CDK6, CDK4 and cyclin D staining (Figure 2k–m) in PFOA-treated cells compared to the control group
Summary
Breast cancer is one of the most common malignancies that women in Western countries may develop in their lifetime (Gullick et al 1998). Several common persistent organic pollutants are endocrine disrupters and proposed to play an important role in cancer etiology These compounds have been linked to effects relevant for the development of breast cancer, including tumor. Human and wildlife monitoring studies have ubiquitously detected manmade perfluoroalkyl acids (PFAAs) throughout the world These chemicals are frequently used in industrial and consumer products, because of their stain-resistant and water-repellant characteristics. MCF-10A is a subline of spontaneously immortalized human breast epithelial cells—derived from human fibrocystic mammary tissue— with characteristics of normal breast epithelium (Soule et al 1990) These features make the MCF-10A a valuable in vitro model for studies of normal breast cell function and determine the potential of environmental contaminants to induce tumor transformation. The findings of this study will help clarify the mechanisms underlying possible effects of PFOA on breast cancer development
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