Abstract
Gene–environment interactions are involved in the development of breast cancer, the tumor type that accounts for the majority of the cancer-related deaths among women. Here, we demonstrate that exposure to PFOS (10 µM) and PFOA (100 µM)—two contaminants ubiquitously found in human blood—for 72 h induced breast epithelial cell (MCF-10A cell line) proliferation and alteration of regulatory cell-cycle proteins (cyclin D1, CDK6, p21, p53, p27, ERK 1/2 and p38) that persisted after a multitude of cell divisions. The contaminants also promoted cell migration and invasion by reducing the levels of E-cadherin, occludin and β-integrin in the unexposed daughter cells. The compounds further induced an increase in global DNA methylation and differentially altered histone modifications, epigenetic mechanisms implicated in tumorigenesis. This mechanistic evidence for PFOS- and PFOA-induced malignant transformation of human breast cells supports a role of these abundant contaminants in the development and progression of breast cancer. Increased knowledge of contaminant-induced effects and their contribution to breast tumorigenesis is important for a better understanding of gene–environment interactions in the etiology of breast cancer.
Highlights
Breast cancer is the most commonly diagnosed cancer among women in the 35–54 age range worldwide and its incidence has increased in almost all Western countries (Brody and Rudel 2003)
The concentrations were chosen based on previous studies where we showed that perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were able to induce MCF-10A cell proliferation and cell invasion (Pierozan et al 2018; Pierozan and Karlsson 2018)
To investigate the mechanisms involved in PFOS and PFOAinduced cell proliferation and alteration of the cell cycle in the daughter cells, the levels of cyclin-dependent kinases (CDK4, CDK6, Cyclin D1) and their respective inhibitors (p27, p21 and p53), as well as some enzymes involved in cell-cycle regulation (ERK, JNK and p38) were analyzed
Summary
Breast cancer is the most commonly diagnosed cancer among women in the 35–54 age range worldwide and its incidence has increased in almost all Western countries (Brody and Rudel 2003). We have recently reported that both of these contaminants are able to induce human epithelial breast cell proliferation and neoplastic transformation via different mechanisms (Pierozan et al 2018; Pierozan and Karlsson 2018). PFOS exposure promoted proliferation and migration/invasion in the human normal breast epithelial cells (MCF-10A) through alteration of regulatory cell-cycle protein levels and acceleration of the cell cycle via ER activation (Pierozan and Karlsson 2018). We investigated the underlying mechanisms, including epigenetic modifications, of PFOS- and PFOA-induced breast epithelial cell transformation, and examined if the effects persist in the absence of the exposure, and are inherited from one cell generation to another for a multitude of cell divisions. This study can contribute to a better understanding of gene–environment interactions in the development of breast cancer
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