MCL1 Inhibition Overcomes the Aggressiveness Features of Triple-Negative Breast Cancer MDA-MB-231 Cells

Abstract

Triple-Negative Breast Cancer (TNBC) is a particularly aggressive subtype among breast cancers (BCs), characterized by anoikis resistance, high invasiveness, and metastatic potential as well as Epithelial–Mesenchymal Transition (EMT) and stemness features. In the last few years, our research focused on the function of MCL1, an antiapoptotic protein frequently deregulated in TNBC. Here, we demonstrate that MCL1 inhibition by A-1210477, a specific BH3-mimetic, promotes anoikis/apoptosis in the MDA-MB-231 cell line, as shown via an increase in proapoptotic markers and caspase activation. Our evidence also shows A-1210477 effects on Focal Adhesions (FAs) impairing the integrin trim and survival signaling pathways, such as FAK, AKT, ERK, NF-κB, and GSK3β-inducing anoikis, thus suggesting a putative role of MCL1 in regulation of FA dynamics. Interestingly, in accordance with these results, we observed a reduction in migratory and invasiveness capabilities as confirmed by a decrease in metalloproteinases (MMPs) levels following A-1210477 treatment. Moreover, MCL1 inhibition promotes a reduction in EMT characteristics as demonstrated by the downregulation of Vimentin, MUC1, DNMT1, and a surprising re-expression of E-Cadherin, suggesting a possible mesenchymal-like phenotype reversion. In addition, we also observed the downregulation of stemness makers such as OCT3/4, SOX2, NANOG, as well as CD133, EpCAM, and CD49f. Our findings support the idea that MCL1 inhibition in MDA-MB-231 could be crucial to reduce anoikis resistance, aggressiveness, and metastatic potential and to minimize EMT and stemness features that distinguish TNBC.

Epithelial-Mesenchymal Transition in Tumor Cells and Activated Intra-Tumor Immunity Respectively Are Correlated With Prognosis and Chemo-Sensitivity in Breast Cancer Patients With a Non-pathological Response to Neoadjuvant Chemotherapy

“…However, this small-scaled exploratory study has indicated that activated intra-tumor immune microenvironments may play an important role in pathological responses to NAC, and that the up-regulation of vimentin and v+ in the residual tumors may be pivotal prognostic factors in non-pCR cases to NAC. Enhancement of intra-tumor immunity before the NAC introduction using pre-operative radiotherapy or immunepotentiating agents might provide a greater anti-tumor activity of NAC [27][28][29]. Additionally, anti-EMT agents together with NAC might improve the outcome of patients with TNBCs [30,31].…”