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."
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."
Williams, M.M., et al. (2019) Therapeutic inhibition of Mcl-1 blocks cell survival in estrogen receptor-positive breast cancers. Oncotarget. doi.org/10.18632/oncotarget.27070.