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

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.

 

Comments:

Your research findings on the role of MCL1 in triple-negative breast cancer (TNBC) are intriguing and suggest a potential therapeutic strategy. Let's break down the key findings and implications of your study:

1. **MCL1 Inhibition and Anoikis/Apoptosis:**
   - The use of A-1210477, a specific BH3-mimetic, inhibits MCL1 and promotes anoikis/apoptosis in the MDA-MB-231 cell line.
   - This is evidenced by an increase in proapoptotic markers and caspase activation.

2. **Effects on Focal Adhesions (FAs) and Survival Signaling Pathways:**
   - A-1210477 affects Focal Adhesions (FAs), impairing integrin trim and survival signaling pathways.
   - Key pathways affected include FAK, AKT, ERK, NF-κB, and GSK3β, ultimately inducing anoikis.

3. **Impact on Migration and Invasiveness:**
   - Treatment with A-1210477 leads to a reduction in migratory and invasive capabilities of MDA-MB-231 cells.
   - This is confirmed by a decrease in metalloproteinases (MMPs) levels following treatment.

4. **EMT Characteristics:**
   - MCL1 inhibition results in a reduction in Epithelial-Mesenchymal Transition (EMT) characteristics.
   - Downregulation of Vimentin, MUC1, DNMT1, and a surprising re-expression of E-Cadherin suggest a possible reversal of the mesenchymal-like phenotype.

5. **Stemness Features:**
   - A-1210477 treatment leads to the downregulation of stemness markers, including OCT3/4, SOX2, NANOG, CD133, EpCAM, and CD49f.

6. **Overall Implications:**
   - The findings suggest that MCL1 inhibition in MDA-MB-231 cells could be crucial in reducing anoikis resistance, aggressiveness, and metastatic potential associated with TNBC.
   - The observed reduction in EMT characteristics and stemness features further supports the potential therapeutic significance of targeting MCL1 in TNBC.

In summary, your research provides valuable insights into the molecular mechanisms underlying the aggressive nature of TNBC and proposes MCL1 inhibition as a potential therapeutic avenue to mitigate these characteristics. Further studies and clinical trials will be essential to validate and translate these findings into effective treatments for patients with TNBC.