BRCA1-associated breast cancers are mostly basal-like high-grade ductal carcinomas that frequently overexpress epidermal growth factor receptor (EGFR). Aberrant EGFR expression is correlated with disease progression, resistance to radiation and chemotherapy, and poor clinical prognosis. While BRCA1 is involved in multiple cellular processes, its functional role in EGFR regulation remains enigmatic. Here, we report a previously unrecognized post-transcriptional mechanism by which BRCA1 regulates EGFR expression through the induction of miR-146a. We demonstrate that EGFR expression correlates negatively with BRCA1, while miR-146a levels increase with BRCA1. We show that BRCA1 binds to miR-146a promoter and activates transcription, which in turn attenuates EGFR expression. Knockdown of miR-146a in BRCA1-overexpressing cells negated this effect and suppressed its ability to inhibit proliferation and transformation. In archived triple negative breast cancer (TNBC) samples, we show a strong positive correlation between BRCA1 and miR-146a expression. We also show that low expression of miR-146a strongly predicts positive lymph node status and is associated with distinctively poor overall survival of patients. Together, these observations provide insight into a novel BRCA1→miR-146a→EGFR paradigm by which BRCA1 carries out an aspect of tumor suppressor function that is potentially amenable to therapeutic intervention.

Malaria remains a worldwide threat, afflicting over 200 million people each year. The emergence of drug resistance against existing therapeutics threatens to destabilize global efforts aimed at controlling Plasmodium spp. parasites, which is expected to leave vast portions of humanity unprotected against the disease. To address this need, systematic testing of a fungal natural product extract library assembled through the University of Oklahoma Citizen Science Soil Collection Program has generated an initial set of bioactive extracts that exhibit potent antiplasmodial activity (EC 50 < 0.30 μg/mL) and low levels of toxicity against human cells (less than 50% reduction in HepG2 growth at 25 μg/mL). Analysis of the two top-performing extracts from Trichoderma sp. and Hypocrea sp. isolates revealed both contained chemically diverse assemblages of putative peptaibol-like compounds that were responsible for their antiplasmodial actions. Purification and structure determination efforts yielded 30 new peptaibols and lipopeptaibols (1−14 and 28−43), along with 22 known metabolites (15−27 and 44−52). While several compounds displayed promising activity profiles, one of the new metabolites, harzianin NPDG I (14), stood out from the others due to its noteworthy potency (EC 50 = 0.10 μM against multi-drugresistant P. falciparum line Dd2) and absence of gross toxicity toward HepG2 at the highest concentrations tested (HepG2 EC 50 > 25 μM, selectivity index > 250). The unique chemodiversity afforded by these fungal isolates serves to unlock new opportunities for translating peptaibols into a bioactive scaffold worthy of further development.

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Natural product drug discovery efforts rely on libraries of organisms to provide access to diverse pools of compounds. Actionable strategies to rationally maximize chemical diversity, rather than relying on serendipity, can add value to such efforts.

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