Therapeutic inhibition of Mcl-1 blocks cell survival in estrogen receptor-positive breast cancers

While estrogen receptor - + breast cancers express high levels of three anti-apoptotic Bcl-2 family members, pharmacological inhibition of Bcl-2 and/or Bcl-xL fails to induce cell death in ER + breast cancer cell lines, due to rapid and robust Mcl-1 upregulation.

Cells treated with a pharmacological inhibitor of cap-dependent translation, or with the mTORC1 inhibitor RAD001/everolimus, displayed reduced protein levels of Mcl-1 under basal conditions, and failed to upregulate Mcl-1 protein expression following treatment with ABT-263, a pharmacological inhibitor of Bcl-2 and Bcl-xL.

Dr. Rebecca S. Cook from Vanderbilt University, in Nashville TN, USA said, "The breast epithelium undergoes many dynamic changes throughout a woman's lifetime."

Figure 1: Pharmacological inhibition of Bcl-2 and/or Bcl-xL increases Mcl-1 expression through cap-dependent translation. (A) Relative MCL1 transcript levels were determined by RT-qPCR after treatment with 1.0 μM ABT-263 for 16 hrs. Values were standardized to DMSO control for each cell line. Each data point represents the average of three technical replicates, midlines are the average of the biological replicates. P-value calculated using Student's unpaired two-tailed t-test. (B–C) Western analysis of lysates from cells treated with 1.0 μM ABT-263 for 16 hrs then chased with cyclohexamide (CHX) for 0-30 minutes. (B) Representative images are shown. Antibodies used are shown to the left of each panel. (C) Average Mcl-1 band density (± S.E.) is shown, N = 3. Two-way ANOVA and Bonferroni post hoc test. (D–F) Western analysis of whole cell lysates were harvested from cell treated with 1.0 μM ABT-263, ABT-199, A-1155463, or ABT-199 + A-1155463 for 16 hrs. Where indicated, 5.0 μM 4E1RCat was added for the final 4 hrs. Antibodies used are shown to the left of each panel.

Specifically, anti-apoptotic Bcl-2 proteins either 1) bind to Bcl-2 effectors to block pore formation in the outer mitochondrial membrane caused by Bak/Bax oligomerization, or 2) sequester Bcl-2 activators, which facilitate Bak/Bax oligomerization.

Estrogen Receptor - positive breast cancer represents 60-70% of all breast cancers diagnosed.

Notably, up to 70% of ER+ breast cancers express Bcl-2, although Bcl-2 is expressed at low levels in other breast cancer subtypes.

In contrast, Bcl-xL and Mcl-1 are widely expressed in ER+ breast cancers, as well as in HER2-amplified and triple negative breast cancers, both in pre-malignant lesions and in high grade tumors.

Similarly, studies in pre-clinical models of ER + breast cancers showed that ABT-263 was ineffective as a single agent, in large part due to rapid Mcl-1 upregulation, although the molecular mechanism driving compensatory Mcl-1 upregulation in response to Bcl-2/Bcl-xL inhibition in ER+ breast cancers are not yet clearly defined.

The Cook research team concluded, "Importantly, we have tested the Mcl-1 selective inhibitor VU661013 in ER+ breast cancer cells, finding that Mcl-1 inhibition increases apoptosis and decreases tumor cell death, particularly when used in combination with ABT-263."

Full text - https://doi.org/10.18632/oncotarget.27070

Correspondence to - Rebecca S. Cook - Rebecca.cook@vanderbilt.edu

Keywords - Mcl-1, ABT-263 resistance, mTORC1 signaling, luminal breast cancers