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Metastatic breast cancer is incurable and often due to breast cancer stem cell (CSC)-mediated self-renewal. We previously determined that aryl hydrocarbon receptor (AhR) agonist aminoflavone (AF) inhibits the expression of CSC biomarker α6-integrin (ITGA6) to disrupt the formation of luminal (hormone receptor-positive) mammospheres (3D breast cancer spheroids). In this study, we performed miRNA-sequencing analysis of luminal A MCF-7 mammospheres treated with AF to gain further insight into the mechanism of AF-mediated anti-cancer and anti-breast CSC activity. AF significantly induced the expression of over 70 miRNAs including miR125b-2-3p, a predicted stemness gene regulator. AF-mediated miR125b-2-3p induction was validated in MCF-7 mammospheres and cells. miR125b-2-3p levels were low in breast cancer tissues irrespective of subtype compared to normal breast tissues. While miR125b-2-3p levels were low in MCF-7 cells, they were much lower in AHR100 cells (MCF-7 cells made unresponsive to AhR agonists). The miR125b-2-3p mimic decreased, while the antagomiR125b-2-3p increased the expression of stemness genes ITGA6 and SOX2 in MCF-7 cells. In MCF-7 mammospheres, the miR125b-2-3p mimic decreased only ITGA6 expression though the antagomiR125b-2-3p increased ITGA6, SOX2 and MYC expression. AntagomiR125b-2-3p reversed AF-mediated suppression of ITGA6. The miR125b-2-3p mimic decreased proliferation, migration, and mammosphere formation while the antagomiR125b-2-3p increased proliferation and mammosphere formation in MCF-7 cells. The miR125b-2-3p mimic also inhibited proliferation, mammosphere formation, and migration in AHR100 cells. AF induced AhR- and miR125b2-3p-dependent anti-proliferation, anti-migration, and mammosphere disruption in MCF-7 cells. Our findings suggest miR125b-2-3p is a tumor suppressor and AF upregulates miR125b-2-3p to disrupt mammospheres via mechanisms that rely at least partially on AhR in luminal A breast cancer cells.

The Petiveria alliacea L. (P. alliacea) plant is traditionally used in folklore medicine throughout tropical regions of the world to treat arthritis, asthma, and cancer. Dibenzyl trisulfide (DTS) is one of the active ingredients within the P. alliacea plant. Triple-negative breast cancer (TNBC) is associated with a poor prognosis, particularly among women of West African ancestry, due in part to limited effective therapy. Though potent anticancer actions of DTS have been reported in a TNBC cell line, the mechanism of DTS-mediated cytotoxicity and cell death remains ill-defined. In the current study, we show that DTS exhibits cytotoxicity in a panel of triple-negative breast cancer (TNBC) cells derived from patients of European and West African ancestry. We found that DTS inhibits proliferation and migration of CRL-2335 cells derived from a patient of West African ancestry. DTS induces the expression of pro-apoptotic genes BAK1, GADD45a, and LTA in CRL2335 cells though it primarily promotes caspase-independent CRL-2335 cell death. DTS also promotes destabilization of the lysosomal membrane resulting in cathepsin B release in CRL-2335 cells. Finally, Kaplan-Meier survival curves reveal that higher expression of BAK1 and LTA in tumors from patients with TNBC is associated with longer relapse-free survival. Collectively, our data suggest that DTS confers promising antitumor efficacy in TNBC, in part, via lysosomal-mediated, caspase-independent cell death to warrant furthering its development as an anticancer agent.

Patients with triple negative breast cancer (TNBC) possess tumors that lack estrogen receptor, progesterone receptor, and human epidermal growth receptor expression. While these patients traditionally receive chemotherapy to combat this aggressive breast cancer subtype, others use natural remedies. Dibenzyl trisulfide (DTS) is derived from Petiveria alliacea, a perennial shrub that grows in tropical regions of the world. Many TNBC patients residing in the tropics are of West African descent. Therefore, we evaluated the anticancer actions of DTS in TNBC cells, including those derived from patients of West African descent. We found that DTS inhibited TNBC cell viability, migration and proliferation in a dose-dependent manner. Interestingly, DTS blocked the propensity of pro-carcinogen benzo-A-pyrene to induce proliferation of immortalized breast epithelial cells. Moreover, we found that DTS induced early apoptosis in TNBC cells, which was only partially attenuated following pretreatment with pan-caspase inhibitor zVAD-fmk. Though DTS induced pro-apoptotic gene and protein expression along with PARP cleavage, it failed to produce appreciable caspase 3 cleavage and promote significant apoptotic body formation. This suggests that this plant isolate induces caspase-independent and non-apoptotic death of TNBC cells. Furthermore, DTS promoted lysosomal membrane destabilization and cathepsin B release in TNBC cells. Taken together, DTS exhibits promising chemotherapeutic and chemopreventive ability by inducing non-apoptotic TNBC cell death and thwarting TNBC progression, supporting its evaluation in clinical trials as an agent to combat TNBC among patients of West African descent. Citation Format: Jonathan Wooten, Shaniece Wooten, Cristina Araújo, Joyce Aja, Nicole Mavingire, Rupika Delgoda, Eileen Brantley. Plant isolate dibenzyl trisulfide induces caspase-independent death in triple negative breast cancer cells derived from patients of West African descent [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-110.

Epigenetics is the study of heritable changes in gene expression without alterations in the underlying DNA sequence. Efforts have been made to understand aspects of epigenetic regulation in normal and cancer cells. With the recent discoveries of key histone methyltransferases, it is an exciting time for the field of epigenetics, particularly for enzymes that have been shown to be the writers of epigenetic markers on genes coding for proteins in cancer. Thus, the development of highly potent and specific small-molecule inhibitors to cancer-related histone methyltransferases shows great promise as a therapeutic option. In this review, we focus on the cancer-related histone methyltransferases, including lysine methyltransferases such as DOT1L, EZH2, G9a, and MLL, as well as arginine methyltransferases. We summarize the enzyme characters, their relations to different cancers, and the drug discoveries targeted to these key enzymes.