The acknowledgment that
pollutants might influence the epigenome raises serious concerns regarding their long-term impact on the development of
chronic diseases. The
herbicide glyphosate has been scrutinized for an impact on
cancer incidence, but reports demonstrate the difficulty of linking estimates of exposure and response analysis. An approach to better apprehend a potential risk impact for
cancer is to follow a synergistic approach, as
cancer rarely occurs in response to one risk factor. The known influence of
glyphosate on
estrogen-regulated pathway makes it a logical target of investigation in
breast cancer research. We have used nonneoplastic MCF10A cells in a repeated
glyphosate exposure pattern over 21 days.
Glyphosate triggered a significant reduction in DNA methylation, as shown by the level of
5-methylcytosine DNA; however, in contrast to strong demethylating agent and
cancer promoter UP
peptide,
glyphosate-treated cells did not lead to
tumor development. Whereas UP acts through a DNMT1/
PCNA/UHRF1 pathway,
glyphosate triggered increased activity of ten-eleven translocation (TET)3. Combining
glyphosate with enhanced expression of
microRNA (miR) 182-5p associated with
breast cancer induced
tumor development in 50% of mice. Culture of primary cells from resected
tumors revealed a
luminal B (ER+/PR-/HER2-) phenotype in response to glyphosate-miR182-5p exposure with sensitivity to
tamoxifen and invasive and migratory potentials.
Tumor development could be prevented either by specifically inhibiting miR 182-5p or by treating
glyphosate-miR 182-5p-cells with
dimethyloxallyl glycine, an inhibitor of TET pathway. Looking for potential epigenetic marks of TET-mediated gene regulation under
glyphosate exposure, we identified MTRNR2L2 and DUX4 genes, the hypomethylation of which was sustained even after stopping
glyphosate exposure for 6 weeks. Our findings reveal that low pressure but sustained
DNA hypomethylation occurring via the TET pathway primes cells for oncogenic response in the presence of another potential risk factor. These results warrant further investigation of
glyphosate-mediated
breast cancer risk.