ERBB2 induces an antiapoptotic expression pattern of Bcl-2 family members in node-negative breast cancer.
OBJECTIVE
Members of the Bcl-2 family act as master regulators of mitochondrial homeostasis and apoptosis. We analyzed whether ERBB2 influences the prognosis of breast cancer by influencing the proapoptotic versus antiapoptotic balance of Bcl-2 family members.


METHODS
ERBB2-regulated Bcl-2 family members were identified by inducible expression of ERBB2 in MCF-7 breast cancer cells and by correlation analysis with ERBB2 expression in breast carcinomas. The prognostic relevance of ERBB2-regulated and all additional Bcl-2 family members was determined in 782 patients with untreated node-negative breast cancer. The biological relevance of ERBB2-induced inhibition of apoptosis was validated in a murine tumor model allowing conditional ERBB2 expression.


RESULTS
ERBB2 caused an antiapoptotic phenotype by upregulation of MCL-1, TEGT, BAG1, BNIP1, and BECN1 as well as downregulation of BAX, BMF, BNIPL, CLU, and BCL2L13. Upregulation of the antiapoptotic MCL-1 [P = 0.001, hazard ratio (HR) 1.5] and BNIP3 (P = 0.024; HR, 1.4) was associated with worse prognosis considering metastasis-free interval, whereas clusterin (P = 0.008; HR, 0.88) and the proapoptotic BCL2L13 (P = 0.019; HR, 0.45) were associated with better prognosis. This indicates that ERBB2 alters the expression of Bcl-2 family members in a way that leads to adverse prognosis. Analysis of apoptosis and tumor remission in a murine tumor model confirmed that the prototypic Bcl-2 family member Bcl-x(L) could partially substitute for ERBB2 to antagonize tumor remission.


CONCLUSIONS
Our results support the concept that ERBB2 influences the expression of Bcl-2 family members to induce an antiapoptotic phenotype. Antagonization of antiapoptotic Bcl-2 family members might improve breast cancer therapy, whereby MCL-1 and BNIP3 represent promising targets.
Petry
Ilka Brigitte
IB
Department of Obstetrics and Gynecology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany. I.Petry@uni-mainz.de
Fieber
Esther
E
Schmidt
Marcus
M
Gehrmann
Mathias
M
Gebhard
Susanne
S
Hermes
Matthias
M
Schormann
Wiebke
W
Selinski
Silvia
S
Freis
Evgenia
E
Schwender
Holger
H
Brulport
Marc
M
Ickstadt
Katja
K
Rahnenführer
Jörg
J
Maccoux
Lindsey
L
West
Jonathan
J
Kölbl
Heinz
H
Schuler
Martin
M
Hengstler
Jan Georg
JG
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D019254:Genes, bcl-2; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D008954:Models, Biological; D005810:Multigene Family / Q000235:genetics; D041681:NIH 3T3 Cells; D020411:Oligonucleotide Array Sequence Analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human