ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins
<p>Dynamic BH3 profiling predicts sensitivity to targeted agents in different ER+ breast cancer cell lines. (<b>A</b>) Results from the DBP assay after 16 h incubation with different treatments in MDA-MB-415 cells. Results expressed as ∆% priming represents the increase in priming compared to control cells. (<b>B</b>) Cell death results from Annexin V and propidium iodide staining and FACS analysis after 72 h incubation with the targeted agents in MDA-MB-415 cells. Results expressed as ∆% cell death represents the increase in cell death compared to control cells. (<b>C</b>) Results from the DBP assay after 16 h incubation with different treatments in T47D cells. Results expressed as ∆% priming represents the increase in priming compared to control cells. (<b>D</b>) Cell death results from Annexin V and propidium iodide staining and FACS analysis after 72 h incubation with the targeted agents in T47D cells. Results expressed as ∆% cell death represents the increase in cell death compared to control cells. (<b>E</b>) Correlation analysis between Δ% priming and Δ% cell death in MDA-MB-415 and T47D cells. (<b>F</b>) Receiver operating characteristic curve analysis. Values indicate mean values ± SEM from at least three independent experiments. ** <span class="html-italic">p</span> < 0.01.</p> "> Figure 1 Cont.
<p>Dynamic BH3 profiling predicts sensitivity to targeted agents in different ER+ breast cancer cell lines. (<b>A</b>) Results from the DBP assay after 16 h incubation with different treatments in MDA-MB-415 cells. Results expressed as ∆% priming represents the increase in priming compared to control cells. (<b>B</b>) Cell death results from Annexin V and propidium iodide staining and FACS analysis after 72 h incubation with the targeted agents in MDA-MB-415 cells. Results expressed as ∆% cell death represents the increase in cell death compared to control cells. (<b>C</b>) Results from the DBP assay after 16 h incubation with different treatments in T47D cells. Results expressed as ∆% priming represents the increase in priming compared to control cells. (<b>D</b>) Cell death results from Annexin V and propidium iodide staining and FACS analysis after 72 h incubation with the targeted agents in T47D cells. Results expressed as ∆% cell death represents the increase in cell death compared to control cells. (<b>E</b>) Correlation analysis between Δ% priming and Δ% cell death in MDA-MB-415 and T47D cells. (<b>F</b>) Receiver operating characteristic curve analysis. Values indicate mean values ± SEM from at least three independent experiments. ** <span class="html-italic">p</span> < 0.01.</p> "> Figure 2
<p>Dynamic BH3 profiling predicts BCL-xL and MCL-1 anti-apoptotic adaptation as a resistance mechanism after targeted agent treatment in ER+ breast cancer cell lines. (<b>A</b>) Results from the contribution of BCL-xL anti-apoptotic protein using the HRK peptide after ipatasertib 1 µM and S63845 1 µM treatment in MDA-MB-415 and T47D. Results expressed as ∆% priming represents the increase in priming compared to control cells. (<b>B</b>,<b>C</b>) Cell death from Annexin V and propidium iodide staining and FACS analysis after 72 h incubation of MDA-MB-415 and T47D cells with the single agents alone or the sequential combination of ipatasertib or S63845 with A-133. (<b>D</b>) DBP from the contribution of MCL-1 anti-apoptotic protein using the MS1 peptide after A-133 0.1 µM treatment. (<b>E</b>,<b>F</b>) Cell death analysis after 72 h incubation of MDA-MB-415 and T47D cells with the single agents alone or the sequential combination of A-133 and S63845 for 72 h. Values indicate mean values ± SEM. ** <span class="html-italic">p</span> < 0.01 compared to single agents and # indicates CI < 1. All experiments were performed at least three times.</p> "> Figure 3
<p>The identified resistant mechanisms are not due to overexpression of anti-apoptotic proteins. Left panel: Representative images from Western blot analysis of T47D control lysates and after treatment with BH3 mimetics for 16 h. Right panel: Optical density quantification normalized to actin and represented as fold change compared to control. S63845 treatment significantly increases MCL-1 expression due to its stabilization. Values indicate mean values ± SEM. * <span class="html-italic">p</span> < 0.05 and all experiments were performed at least three times.</p> "> Figure 4
<p>The acquired resistance mechanisms are controlled by the amount of anti-apoptotic protein bound to BIM. (<b>A</b>) Upper panel: Representative images of Western blot analysis of T47D cell lysates and unbound fractions after BIM immunoprecipitation. Lower panel: Optical density quantification of BIM normalized with actin levels and represented as fold increase compared to the control condition RabIgG. (<b>B</b>) Upper panel: Representative images of Western blot analysis of T47D cell lysates after 16 h treatment with the indicated drugs. Lower panel: Optical density quantification of each protein normalized to actin and represented as fold increase compared to control cells (<b>C</b>) Left panel: Representative images of Western blot analysis of BIM immunoprecipitation in T47D cells. Right panel: Quantification of the optical density of each protein and represented as binding ratio between BIM and MCL-1 or BCL-xL. Results expressed as fold increase represents the increase in optical density after treatments compared to control cells. Values indicate mean values ± SEM. ** <span class="html-italic">p</span> < 0.01, * <span class="html-italic">p</span> < 0.05 and all experiments were performed at least three times.</p> "> Figure 5
<p>Schematic representation of MCL-1 and BCL-xL interaction with BIM as a therapy-acquired resistance mechanism. The model distinguishing mechanisms that may operate in the presence of either S63845, A-133, or the sequential combination of both BH3 mimetics. The interaction of BIM with MCL-1 and A-133 would shift depending on the BH3 mimetic used, conferring cell death protection. Only when we sequentially combined both BH3 mimetics, cells will undergo apoptotic cell death.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Lines and Treatments
2.2. Dynamic BH3 Profiling
2.3. Cell Death Analysis
2.4. Protein Extraction and Quantification
2.5. Immunoprecipitation
2.6. Immunoblotting
2.7. Statistical Analysis
3. Results
3.1. Dynamic BH3 Profiling Predicts Targeted Agents’ Effectiveness in ER+ Breast Cancer Cells
3.2. Inhibition of Anti-Apoptotic Adaptations Could Overcome Treatment-Induced Resistance
3.3. Resistance to Treatments Relies on BCL-xL and MCL-1 Binding to BIM
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Alcon, C.; Gómez Tejeda Zañudo, J.; Albert, R.; Wagle, N.; Scaltriti, M.; Letai, A.; Samitier, J.; Montero, J. ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins. Cells 2021, 10, 1659. https://doi.org/10.3390/cells10071659
Alcon C, Gómez Tejeda Zañudo J, Albert R, Wagle N, Scaltriti M, Letai A, Samitier J, Montero J. ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins. Cells. 2021; 10(7):1659. https://doi.org/10.3390/cells10071659
Chicago/Turabian StyleAlcon, Clara, Jorge Gómez Tejeda Zañudo, Reka Albert, Nikhil Wagle, Maurizio Scaltriti, Anthony Letai, Josep Samitier, and Joan Montero. 2021. "ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins" Cells 10, no. 7: 1659. https://doi.org/10.3390/cells10071659