The transcription factor ZNF217 is a prognostic biomarker and therapeutic target during breast cancer progression.
The transcription factor ZNF217 is a candidate oncogene in the amplicon on chromosome 20q13 that occurs in 20% to 30% of primary human breast cancers and that correlates with poor prognosis. We show that Znf217 overexpression drives aberrant differentiation and signaling events, promotes increased self-renewal capacity, mesenchymal marker expression, motility, and metastasis, and represses an adult tissue stem cell gene signature downregulated in cancers. By in silico screening, we identified candidate therapeutics that at low concentrations inhibit growth of cancer cells expressing high ZNF217. We show that the nucleoside analogue triciribine inhibits ZNF217-induced tumor growth and chemotherapy resistance and inhibits signaling events [e.g., phospho-AKT, phospho-mitogen-activated protein kinase (MAPK)] in vivo. Our data suggest that ZNF217 is a biomarker of poor prognosis and a therapeutic target in patients with breast cancer and that triciribine may be part of a personalized treatment strategy in patients overexpressing ZNF217. Because ZNF217 is amplified in numerous cancers, these results have implications for other cancers.


CONCLUSIONS
This study finds that ZNF217 is a poor prognostic indicator and therapeutic target in patients with breast cancer and may be a strong biomarker of triciribine treatment efficacy in patients. Because previous clinical trials for triciribine did not include biomarkers of treatment efficacy, this study provides a rationale for revisiting triciribine in the clinical setting as a therapy for patients with breast cancer who overexpress ZNF217.
Department of Anatomy, University of California, San Francisco, CA 94143, USA.
Laurie E
LE
Littlepage
Adam S
AS
Adler
Hosein
H
Kouros-Mehr
Guiqing
G
Huang
Jonathan
J
Chou
Sheryl R
SR
Krig
Obi L
OL
Griffith
James E
JE
Korkola
Kun
K
Qu
Devon A
DA
Lawson
Qing
Q
Xue
Mark D
MD
Sternlicht
Gerrit J P
GJ
Dijkgraaf
Paul
P
Yaswen
Hope S
HS
Rugo
Colleen A
CA
Sweeney
Colin C
CC
Collins
Joe W
JW
Gray
Howard Y
HY
Chang
Zena
Z
Werb
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D041681:NIH 3T3 Cells; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012263:Ribonucleosides / Q000494:pharmacology; D016019:Survival Analysis; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D012263:Ribonucleosides; D015534:Trans-Activators; C113698:ZNF217 protein, human; C023764:triciribine; D004317:Doxorubicin