A functional and regulatory network associated with PIP expression in human breast cancer.
BACKGROUND
The PIP (prolactin-inducible protein) gene has been shown to be expressed in breast cancers, with contradictory results concerning its implication. As both the physiological role and the molecular pathways in which PIP is involved are poorly understood, we conducted combined gene expression profiling and network analysis studies on selected breast cancer cell lines presenting distinct PIP expression levels and hormonal receptor status, to explore the functional and regulatory network of PIP co-modulated genes.


RESULTS
Microarray analysis allowed identification of genes co-modulated with PIP independently of modulations resulting from hormonal treatment or cell line heterogeneity. Relevant clusters of genes that can discriminate between [PIP+] and [PIP-] cells were identified. Functional and regulatory network analyses based on a knowledge database revealed a master network of PIP co-modulated genes, including many interconnecting oncogenes and tumor suppressor genes, half of which were detected as differentially expressed through high-precision measurements. The network identified appears associated with an inhibition of proliferation coupled with an increase of apoptosis and an enhancement of cell adhesion in breast cancer cell lines, and contains many genes with a STAT5 regulatory motif in their promoters.


CONCLUSIONS
Our global exploratory approach identified biological pathways modulated along with PIP expression, providing further support for its good prognostic value of disease-free survival in breast cancer. Moreover, our data pointed to the importance of a regulatory subnetwork associated with PIP expression in which STAT5 appears as a potential transcriptional regulator.
Debily
Marie-Anne
MA
Array s/IMAGE, Genexpress, Functional Genomics and Systems Biology for Health, LGN-UMR 7091-CNRS and Pierre & Marie Curie University, Paris VI, Villejuif, France. marie-anne.debily@cea.fr
Marhomy
Sandrine El
SE
Boulanger
Virginie
V
Eveno
Eric
E
Mariage-Samson
Régine
R
Camarca
Alessandra
A
Auffray
Charles
C
Piatier-Tonneau
Dominique
D
Imbeaud
Sandrine
S
D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics*; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016000:Cluster Analysis; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006023:Glycoproteins / Q000032:analysis / Q000235:genetics*; D006801:Humans; D026901:Membrane Transport Proteins; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011401:Promoter Regions, Genetic; D050799:STAT5 Transcription Factor / Q000502:physiology*
D002352:Carrier Proteins; D006023:Glycoproteins; D026901:Membrane Transport Proteins; C488892:PIP protein, human; D050799:STAT5 Transcription Factor