Multifaceted impact of HIV inhibitor dapivirine on triple negative breast cancer cells reveals potential entities as targets for novel therapy

Breast cancer is the most common cancer in women worldwide. Many breast cancers originate from the cells lining the milk duct and some become invasive. Breast cancer lacking estrogen, progesterone receptors (ER-, PR-) and epidermal growth factor receptor 2 (HER2-) amplification, termed "Triple negative" (TNBC) is reported to frequently affect Black women and younger women. TNBC is an invasive ductal carcinoma with limited treatment options. To this end, we opted to investigate drugs that could be repurposed because they offer advantages in bringing effective treatments faster to the clinic. We chose to study the effect of the drug, dapivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV because it could be detected in the breast milk of lactating women when treated for HIV and the drug could potentially target the cancer. Here we show the potent impact of dapivirine on MDA-MB-231 TNBC cells, while NNRTI like nevirapine showed marginal effects. When dapivirine was tested on other breast cell lines, MCF-7 and MCF 10A, the inhibition was at higher concentrations. Molecular studies with dapivirine in TNBC cells, revealed an increase in reactive oxygen species (ROS), apoptotic cells, and activation of caspases. Importantly, protein profiling and STRING analysis revealed deregulation of the key molecule, PCNA and impact on pivotal cell signaling circuits including extracellular matrix (ECM), angiogenesis, cell adhesion, and immunomodulation. Of note, is its potential effect on stem-like cells due to downregulation of the basic transcription factor 3 (BTF3) and proteasome activator complex subunit 3; the latter affecting their dependence on the proteasome pathway. Taken together, dapivirine exhibits the potential to be considered as a repurposed drug for TNBC as monotherapy/combination therapy. Notably, it could also potentially be a treatment for individuals with dual ailments, such as HIV and TNBC, if the clinical outcomes with dapivirine for TNBC become favorable.