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

// Michelle M. Williams 1 , Rebecca S. Cook 1, 2 1 Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville TN 27232, USA 2 Department of Vanderbilt Ingram Cancer Center, Nashville, TN 37232, USA Correspondence to: Rebecca S. Cook, e-mail: Rebecca.cook@vanderbilt.edu Received: August 27, 2014 Accepted: November 20, 2014 Published: February 12, 2015 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.