Frequent PTEN genomic alterations and activated phosphatidylinositol 3-kinase pathway in basal-like breast cancer cells.
BACKGROUND
Basal-like carcinomas (BLCs) and human epidermal growth factor receptor 2 overexpressing (HER2+) carcinomas are the subgroups of breast cancers that have the most aggressive clinical behaviour. In contrast to HER2+ carcinomas, no targeted therapy is currently available for the treatment of patients with BLCs. In order to discover potential therapeutic targets, we aimed to discover deregulated signalling pathways in human BLCs.


METHODS
In this study, we focused on the oncogenic phosphatidylinositol 3-kinase (PI3K) pathway in 13 BLCs, and compared it with a control series of 11 hormonal receptor negative- and grade III-matched HER2+ carcinomas. The two tumour populations were first characterised by immunohistochemistry and gene expression. The PI3K pathway was then investigated by gene copy-number analysis, gene expression profiling and at a proteomic level using reverse-phase protein array technology and tissue microarray. The effects of the PI3K inhibition pathway on proliferation and apoptosis was further analysed in three human basal-like cell lines.


RESULTS
The PI3K pathway was found to be activated in BLCs and up-regulated compared with HER2+ tumours as shown by a significantly increased activation of the downstream targets Akt and mTOR (mammalian target of rapamycin). BLCs expressed significantly lower levels of the tumour suppressor PTEN and PTEN levels were significantly negatively correlated with Akt activity within that population. PTEN protein expression correlated significantly with PTEN DNA copy number and more importantly, reduced PTEN DNA copy numbers were observed specifically in BLCs. Similar to human samples, basal-like cell lines exhibited an activation of PI3K/Akt pathway and low/lack PTEN expression. Both PI3K and mTOR inhibitors led to basal-like cell growth arrest. However, apoptosis was specifically observed after PI3K inhibition.


CONCLUSIONS
These data provide insight into the molecular pathogenesis of BLCs and implicate the PTEN-dependent activated Akt signalling pathway as a potential therapeutic target for the management of patients with poor prognosis BLCs.
Marty
Bérengère
B
Département de Transfert, Institut Curie, 26 rue d'Ulm, 75005 Paris, France.
Maire
Virginie
V
Gravier
Eléonore
E
Rigaill
Guillem
G
Vincent-Salomon
Anne
A
Kappler
Marion
M
Lebigot
Ingrid
I
Djelti
Fathia
F
Tourdès
Audrey
A
Gestraud
Pierre
P
Hupé
Philippe
P
Barillot
Emmanuel
E
Cruzalegui
Francisco
F
Tucker
Gordon C
GC
Stern
Marc-Henri
MH
Thiery
Jean-Paul
JP
Hickman
John A
JA
Dubois
Thierry
T
D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018295:Neoplasms, Basal Cell / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D040081:Protein Array Analysis; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured
D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C494929:PTEN protein, human