title: Key Survival Factor, Mcl-1, Correlates with Sensitivity to Combined Bcl-2/Bcl-xL Blockade.
abstract: An estimated 40,000 deaths will be attributed to breast cancer in 2016, underscoring the need for improved therapies. Evading cell death is a major hallmark of cancer, driving tumor progression and therapeutic resistance. To evade apoptosis, cancers use antiapoptotic Bcl-2 proteins to bind to and neutralize apoptotic activators, such as Bim. Investigation of antiapoptotic Bcl-2 family members in clinical breast cancer datasets revealed greater expression and more frequent gene amplification ofMCL1as compared withBCL2orBCL2L1(Bcl-xL) across three major molecular breast cancer subtypes, Luminal (A and B), HER2-enriched, and Basal-like. While Mcl-1 protein expression was elevated in estrogen receptor α (ERα)-positive and ERα-negative tumors as compared with normal breast, Mcl-1 staining was higher in ERα+tumors. Targeted Mcl-1 blockade using RNAi increased caspase-mediated cell death in ERα+breast cancer cells, resulting in sustained growth inhibition. In contrast, combined blockade of Bcl-2 and Bcl-xL only transiently induced apoptosis, as cells rapidly acclimated through Mcl-1 upregulation and enhanced Mcl-1 activity, as measuredin situusing Mcl-1/Bim proximity ligation assays. Importantly,MCL1gene expression levels correlated inversely with sensitivity to pharmacologic Bcl-2/Bcl-xL inhibition in luminal breast cancer cells, whereas no relationship was seen between the gene expression ofBCL2orBCL2L1and sensitivity to Bcl-2/Bcl-xL inhibition. These results demonstrate that breast cancers rapidly deploy Mcl-1 to promote cell survival, particularly when challenged with blockade of other Bcl-2 family members, warranting the continued development of Mcl-1-selective inhibitors for targeted tumor cell killing.Implications:Mcl-1 levels predict breast cancer response to inhibitors targeting other Bcl-2 family members, and demonstrate the key role played by Mcl-1 in resistance to this drug class.Mol Cancer Res; 15(3); 259-68. ©2016 AACR.
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Williams
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.
authors.forename: Linus
authors.initials: L
authors.lastname: Lee
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Hicks
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Meghan M
authors.initials: MM
authors.lastname: Joly
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: David
authors.initials: D
authors.lastname: Elion
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Bushra
authors.initials: B
authors.lastname: Rahman
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Courtney
authors.initials: C
authors.lastname: McKernan
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Violeta
authors.initials: V
authors.lastname: Sanchez
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.|Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Balko
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.|The Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stricker
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Monica Valeria
authors.initials: MV
authors.lastname: Estrada
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee. Rebecca.cook@vanderbilt.edu.|Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.|The Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Cook
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; C494811:BCL2L1 protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D013449:Sulfonamides; D051020:bcl-X Protein; C528561:navitoclax