PTTG1 overexpression in adrenocortical cancer is associated with poor survival and represents a potential therapeutic target.
BACKGROUND
Adrenocortical carcinoma (ACC) is associated with poor survival rates. The objective of the study was to analyze ACC gene expression profiling data for prognostic biomarkers and therapeutic targets.


METHODS
We profiled 44 ACC and 4 normal adrenals on Affymetrix U133 Plus 2 expression microarrays. Pathway and transcriptional enrichment analysis was performed. Protein levels were determined by Western blot. Drug efficacy was assessed against ACC cell lines. Previously published expression datasets were analyzed for validation.


RESULTS
Pathway enrichment analysis identified marked dysregulation of cyclin-dependent kinases and mitosis. Overexpression of PTTG1, which encodes securin, a negative regulator of p53, was identified as a marker of poor survival. Median survival for patients with tumors expressing high PTTG1 levels (log2 ratio of PTTG1 to average β-actin <-3.04) was 1.8 years compared with 9.0 years if tumors expressed lower levels of PTTG1 (P < .0001). Analysis of a previously published dataset confirmed the association of high PTTG1 expression with a poor prognosis. Treatment of 2 ACC cell lines with vorinostat decreased securin levels and inhibited cell growth (median inhibition concentrations of 1.69 μmol/L and 0.891 μmol/L, for SW-13 and H295R, respectively).


CONCLUSIONS
Overexpression of PTTG1 is correlated with poor survival in ACC. PTTG1/securin is a prognostic biomarker and warrants investigation as a therapeutic target.
Translational Genomics Research Institute, Phoenix, AZ. Electronic address: mdemeure@tgen.org.
Michael J
MJ
Demeure
Kathryn E
KE
Coan
Clive S
CS
Grant
Richard A
RA
Komorowski
Elizabeth
E
Stephan
Shripad
S
Sinari
David
D
Mount
Kimberly J
KJ
Bussey
D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018268:Adrenocortical Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D064249:Securin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000077337:Vorinostat; D055815:Young Adult
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D006877:Hydroxamic Acids; D064249:Securin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C578002:pituitary tumor-transforming protein 1, human; D000077337:Vorinostat