A systems analysis of the chemosensitivity of breast cancer cells to the polyamine analogue PG-11047.
BACKGROUND
Polyamines regulate important cellular functions and polyamine dysregulation frequently occurs in cancer. The objective of this study was to use a systems approach to study the relative effects of PG-11047, a polyamine analogue, across breast cancer cells derived from different patients and to identify genetic markers associated with differential cytotoxicity.


METHODS
A panel of 48 breast cell lines that mirror many transcriptional and genomic features present in primary human breast tumours were used to study the antiproliferative activity of PG-11047. Sensitive cell lines were further examined for cell cycle distribution and apoptotic response. Cell line responses, quantified by the GI50 (dose required for 50% relative growth inhibition) were correlated with the omic profiles of the cell lines to identify markers that predict response and cellular functions associated with drug sensitivity.


RESULTS
The concentrations of PG-11047 needed to inhibit growth of members of the panel of breast cell lines varied over a wide range, with basal-like cell lines being inhibited at lower concentrations than the luminal cell lines. Sensitive cell lines showed a significant decrease in S phase fraction at doses that produced little apoptosis. Correlation of the GI50 values with the omic profiles of the cell lines identified genomic, transcriptional and proteomic variables associated with response.


CONCLUSIONS
A 13-gene transcriptional marker set was developed as a predictor of response to PG-11047 that warrants clinical evaluation. Analyses of the pathways, networks and genes associated with response to PG-11047 suggest that response may be influenced by interferon signalling and differential inhibition of aspects of motility and epithelial to mesenchymal transition.
Kuo
Wen-Lin
WL
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA. wlkuo@lbl.gov
Das
Debopriya
D
Ziyad
Safiyyah
S
Bhattacharya
Sanchita
S
Gibb
William J
WJ
Heiser
Laura M
LM
Sadanandam
Anguraj
A
Fontenay
Gerald V
GV
Hu
Zhi
Z
Wang
Nicholas J
NJ
Bayani
Nora
N
Feiler
Heidi S
HS
Neve
Richard M
RM
Wyrobek
Andrew J
AJ
Spellman
Paul T
PT
Marton
Laurence J
LJ
Gray
Joe W
JW
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology
C415967:(N(1),N(12))bis(ethyl)-6,7-dehydrospermine; D000970:Antineoplastic Agents; D013096:Spermine