Bcl-2 family proteins in breast development and cancer: could Mcl-1 targeting overcome therapeutic resistance?

Abstract

Apoptosis, cell death executed by caspases, is essential to normal breast development and homeostasis. Pro-apoptotic and anti-apoptotic signals are tightly regulated in normal breast epithelial cells. Dysregulation of this balance is required for breast tumorigenesis and increases acquired resistance to treatments, including molecularly targeted therapies, radiation and chemotherapies. The pro-apoptotic or anti-apoptotic Bcl-2 family members interact with each other to maintain mitochondrial integrity and regulate cellular commitment to apoptosis. Among the anti-apoptotic Bcl-2 family members, Mcl-1 is uniquely regulated by numerous oncogenic signaling pathways. This review will focus on the role of Bcl-2 family proteins in normal breast development, breast tumorigenesis and acquired resistance to breast cancer treatment strategies, while highlighting Mcl-1 as a promising target to improve breast cancer tumor cell killing.

Figure 1

(A) Bcl-2 family member effector proteins (Bax and Bak) oligomerize and permeablize the outer mitochondrial membrane (OMM) upon activator-protein (Bid, Bim and Puma) bindingCytochrome-c is able to escape the mitochondria through Bak/Bax pores, leading to caspase cleavage and apoptosis. Anti-apoptotic Bcl-2 family members (A1, Bcl-2, Bcl-xL, Bcl-w and Mcl-1) inhibit apoptosis by preventing effector protein oligomerization or Bak/Bax activation. Sensitizer proteins (Bad, Bik and Noxa) counteract anti-apoptotic members by sequestering anti-apoptotic proteins. (B) When the balance of active Bcl-2 proteins favors pro-apoptotic over anti-apoptotic family members, apoptosis is initiated. (C–D) Proposed models of Mcl-1 expression or activity supporting resistance to standard chemotherapies or targeted therapies (C) and BH3-mimetics (B).

Figure 2

(A) Transcriptional, translational and post translational mechanisms of Mcl-1 regulation (promoters support Mcl-1 expression, while deregulators decrease Mcl-1 expression). (B–C) A complex interplay of phosphatases (B), ubiquitinases and deubiquitinases (DUBs) (C) regulate Mcl-1 stability through activation or suppression of ubiquitin-mediated proteasomal degradation of Mcl-1 (further reviewed in [55, 56]).

Figure 3. Expression signature of Bcl-2 family proteins in human breast cancer cell lines according to the cancer cell line encyclopedia as curated by the cancer genome atlas

(BCL2L11 = BIM, BBC3 = PUMA, PMAIP1 = NOXA, BCL2L1 = Bcl-xL, BCL2L2 = Bcl-w).