LAUSR

Methylparaben (MP) and propylparaben (PP) are commonly used as food, cosmetic, and drug preservatives. These parabens are detected in the majority of US women and children, bind and activate estrogen receptors (ER), and stimulate mammary tumor cell growth and invasion in vitro. Hemizygous B6.FVB-Tg (MMTV-PyVT)634Mul/LellJ female mice (n = 20/treatment) were exposed to MP or PP at levels within the United States Food and Drug Administration's "human acceptable daily intake". These paraben exposed mice had increased mammary tumor volume compared to control mice (p < 0.001) and a 28% and 91% increase in the number of pulmonary metastases per week compared to the control mice, respectively (p < 0.0001). MP and PP caused differential expression of 288 and 412 mammary tumor genes, respectively (FDR < 0.05), a subset of which has been associated with human breast cancer metastasis. Molecular docking and luciferase reporter studies affirmed that MP and PP bound and activated human ER, and RNA-seq revealed increased ER expression in mammary tumors among paraben exposed mice. However, ER signaling was not enriched in mammary tumors. Instead, both parabens strongly impaired tumor RNA metabolism, e.g., ribosome and spliceosome, as evident from enriched KEGG pathway analysis of differential mammary tumor gene expression common to both paraben treatments (MP p < 0.001; PP p < 0.01). Indeed mammary tumors from PP exposed mice had an increased retention of introns (p < 0.05). Our data suggest that parabens cause substantial mammary cancer metastasis in mice as a function of their increasing alkyl chain length and highlight the emerging role of aberrant spliceosome activity in breast cancer metastasis.