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Triple negative breast cancer (TNBC) is a highly aggressive, heterogeneous disease with high rates of metastasis and poor prognosis. Currently, there are no targeted therapies for TNBC and adjuvant chemotherapy is the mainstay treatment. Identification of molecular targets and potent combination therapies for TNBC is a major challenge of extensive biomedical research and our own studies. Given that drug resistance is a critical clinical problem, a drug combination that could overcome drug resistance could offer a promising therapeutic opportunity. We have recently identified potent combination therapies for TNBC which are not only potent but could also overcome drug resistance and further defined the molecular mechanisms underlying their therapeutic benefit.

Wastewater treatment plants consolidate high loads of fecal and environmental bacteria and residual concentrations of antibiotics and consequentially, effluents released from these facilities may contribute to antibiotic resistance in downstream ecosystems. This is especially relevant in arid and semi-arid environments, where treated wastewater (TWW) is used for irrigation. The goal of this study was to pinpoint key antibiotic resistance genes (ARGs) in wastewater effluents and to determine the impact of TWW irrigation on antibiotic resistance in terrestrial and food-associated microbiomes. The diversity and abundance of ARGs was evaluated in wastewater effluents, in TWW -irrigated soils and in crops irrigated with TWW using state of the art molecular, genomic and bioinformatic analyses. Three specific methods were applied: (A) a novel high-throughput amplicon sequencing methodology that specifically targeted ARGs associated with integron gene cassettes in effluents from 12 wastewater treatment facilities across Europe and in pristine vs. wastewater effluent-saturated soil; (B) quantitative PCR that assessed the abundance of selected ARGs along freshwater- and TWW-irrigated, water-soil-crop continuum; and (C) comparative in-silico-based analyses of human gut, wastewater and soil metagenomes to determine specific associations between wastewater and soil resistomes. Our results reveal that wastewater effluents contain a diverse array of ARGs, and that specific ARGs and class 1 integrons (mobile genetic elements that often harbor ARGs) are profuse and strongly associated with wastewater effluents. In contrast we found that other ARGs that are ubiquitous to soil regardless of TWW irrigation suggesting that these elements are common in environmental microbiomes. Collectively, the study indicates the distribution of ARGs in the environment is highly complex and is impacted by both natural and anthropogenic factors, and that while the impact of wastewater-derived ARGs in TWW-irrigated soils is limited, there is evidence that plasmid- and integron-associated ARGs are disseminated to soil microbiomes.