Polycyclic aromatic hydrocarbon (PAH) exposure is widespread, and many PAHs are considered carcinogenic. The PAH-contaminated AWI Superfund site in Virginia provides a model for studying a complex PAH mixture and its extrapolation to cancer risk and PAH exposure in the general population. We examined cancer risk at the Superfund site due to sediment-derived PAHs and then evaluated PAH sources in the general population and potentially vulnerable subpopulations upon PAH mixture exposure. The PAH mixture was assessed for potential carcinogenicity using the US EPA's OncoLogic™ ranking tool and the US EPA list of priority PAHs. Cancer risk due to PAH exposure was calculated for Superfund site users and compared to the US EPA assessment. Human intake and health endpoints of PAHs within the mixture were extracted from USEtox® chemical fate database, while mean intake exposure was calculated for U.S. adults for select PAHs using NHANES database urinary biomarkers. Eleven PAH compounds within the mixture were of carcinogenic concern, and seven PAHs conveyed significant excess cancer risk at the Superfund site and in the general population, wherein PAH-contaminated seafood ingestion was a main contributor. Other dietary sources of PAHs derived from PAH-contaminated soil or water could also play a role in total exposure. Vulnerable populations to PAH exposure and coinciding increased cancer risk may include, in addition to smokers, children and non-Hispanic blacks, which is a public health concern.

Triple-negative breast cancer (TNBC) has high relapse and metastasis rates and a high proportion of cancer stem-like cells (CSCs), which possess self-renewal and tumor initiation capacity. MELK (maternal embryonic leucine zipper kinase), a protein kinase of the Snf1/AMPK kinase family, is known to promote CSC maintenance and malignant transformation. However, the role of MELK in TNBC metastasis is unknown; we sought to address this in the current study. We found that MELK mRNA levels were higher in TNBC tumors (8.11 [3.79-10.95]) than in HR+HER2- tumors (6.54 [2.90-9.26]; P < 0.001). In univariate analysis, breast cancer patients with high-MELK-expressing tumors had worse overall survival (P < 0.001) and distant metastasis-free survival (P < 0.01) than patients with low-MELK-expressing tumors. In a multicovariate Cox regression model, high MELK expression was associated with shorter overall survival after adjusting for other baseline risk factors. MELK knockdown using siRNA or MELK inhibition using the MELK inhibitor MELK-In-17 significantly reduced invasiveness, reversed epithelial-to-mesenchymal transition, and reduced CSC self-renewal and maintenance in TNBC cells. Nude mice injected with CRISPR MELK-knockout MDA-MB-231 cells exhibited suppression of lung metastasis and improved overall survival compared with mice injected with control cells (P < 0.05). Furthermore, MELK-In-17 suppressed 4T1 tumor growth in syngeneic BALB/c mice (P < 0.001). Our findings indicate that MELK supports metastasis by promoting epithelial-to-mesenchymal transition and the CSC phenotype in TNBC. Significance: These findings indicate that MELK is a driver of aggressiveness and metastasis in TNBC.

No abstract