Abstract
It is of utmost importance to decipher the role of chronic exposure to low doses of environmental carcinogens on breast cancer progression. The early-transformed triple-negative human mammary MCF10AT1 cells were chronically (60 days) exposed to low doses (10−10 M) of Benzo[a]pyrene (B[a]P), a genotoxic agent, and/or Bisphenol A (BPA), an endocrine disruptor. Our study revealed that exposed MCF10AT1 cells developed, in a time-dependent manner, an acquired phenotype characterized by an increase in cancerous properties (anchorage independent growth and stem-like phenotype). Co-exposure of MCF10AT1 cells to B[a]P and BPA led to a significantly greater aggressive phenotype compared to B[a]P or BPA alone. This study provided new insights into the existence of a functional interplay between the aryl hydrocarbon receptor (AhR) and the G protein-coupled receptor 30 (GPR30) by which chronic and low-dose exposure of B[a]P and/or BPA fosters the progression of MCF10AT1 cells into a more aggressive substage. Experiments using AhR or GPR30 antagonists, siRNA strategies, and RNAseq analysis led us to propose a model in which AhR signaling plays a “driver role” in the AhR/GPR30 cross-talk in mediating long-term and low-dose exposure of B[a]P and/or BPA. Retrospective analysis of two independent breast cancer cohorts revealed that the AhR/GPR30 mRNA expression signature resulted in poor breast cancer prognosis, in particular in the ER-negative and the triple-negative subtypes. Finally, the study identified targeting AhR and/or GPR30 with specific antagonists as a strategy capable of inhibiting carcinogenesis associated with chronic exposure to low doses of B[a]P and BPA in MCF10AT1 cells. Altogether, our results indicate that the engagement of both AhR and GPR30 functions, in particular in an ER-negative/triple-negative context of breast cells, favors tumor progression and leads to poor prognosis.
Highlights
Progression of human breast epithelial cells from non-cancerous to pre-malignant and of early-transformed mammary cells to malignant stages is a multiyear, multistep, multiscale, and multipath disease process
The main objectives of this work were to newly investigate: (i) whether long-term and low-dose exposure to B[a]P and/or BPA triggers the progression of early-transformed mammary cells to a more aggressive stage; (ii) whether their combination enhances the effect of each compound tested individually, in particular whether BPA facilitates the pro-carcinogenic activity of B[a]P; and (iii) to identify candidate strategies capable of inhibiting mammary carcinogenesis linked to chronic exposure to the environmental pollutants B[a]P and/or BPA
Validation of progression to malignancy of MCF10AT1 cells was investigated by assessing: (i) anchorage-independent growth (AIG), a hallmark of carcinogenesis associated with aggressiveness and metastasis in malignant cells; (ii) cancer stem-like and selfrenewing properties by assessing first and second generation mammosphere-forming efficiency (MFE), as a growing body of evidence suggests that cancer stem-like cells are involved in generating and maintaining pre-malignant and malignant lesions [55,56,57]
Summary
Progression of human breast epithelial cells from non-cancerous to pre-malignant and of early-transformed mammary cells to malignant stages is a multiyear, multistep, multiscale, and multipath disease process. Given the increasing evidence that common environmental carcinogens play a significant role in breast cancer, increased attention has been paid to molecular mechanisms through which pollutants affect breast tumor formation, progression, and/or invasion [6,7,8]. The identification of such molecular mechanisms could have several societal and environmental consequences, and may lead to the discovery of human biomarkers of exposure to environmental carcinogens exploitable for breast cancer prevention. Few studies have attempted to mimic natural environmental exposure by assessing the impact of exposure to a combination of several pollutants with distinct mechanisms of action that may interact or induce a greater adverse effect than the use of individual compounds
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