PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer.
PIK3CA mutations are reported to be present in approximately 25% of breast cancer (BC), particularly the estrogen receptor-positive (ER+) and HER2-overexpressing (HER2+) subtypes, making them one of the most common genetic aberrations in BC. In experimental models, these mutations have been shown to activate AKT and induce oncogenic transformation, and hence these lesions have been hypothesized to render tumors highly sensitive to therapeutic PI3K/mTOR inhibition. By analyzing gene expression and protein data from nearly 1,800 human BCs, we report that a PIK3CA mutation-associated gene signature (PIK3CA-GS) derived from exon 20 (kinase domain) mutations was able to predict PIK3CA mutation status in two independent datasets, strongly suggesting a characteristic set of gene expression-induced changes. However, in ER+/HER2- BC despite pathway activation, PIK3CA mutations were associated with a phenotype of relatively low mTORC1 signaling and a good prognosis with tamoxifen monotherapy. The relationship between clinical outcome and the PIK3CA-GS was also assessed. Although the PIK3CA-GS was not associated with prognosis in ER- and HER2+ BC, it could identify better clinical outcomes in ER+/HER2- disease. In ER+ BC cell lines, PIK3CA mutations were also associated with sensitivity to tamoxifen. These findings could have important implications for the treatment of PIK3CA-mutant BCs and the development of PI3K/mTOR inhibitors.
Loi
Sherene
S
Department of Research, Molecular Oncology Laboratory, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia. sherene.loi@bordet.be
Haibe-Kains
Benjamin
B
Majjaj
Samira
S
Lallemand
Francoise
F
Durbecq
Virginie
V
Larsimont
Denis
D
Gonzalez-Angulo
Ana M
AM
Pusztai
Lajos
L
Symmans
W Fraser
WF
Bardelli
Alberto
A
Ellis
Paul
P
Tutt
Andrew N J
AN
Gillett
Cheryl E
CE
Hennessy
Bryan T
BT
Mills
Gordon B
GB
Phillips
Wayne A
WA
Piccart
Martine J
MJ
Speed
Terence P
TP
McArthur
Grant A
GA
Sotiriou
Christos
C
D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D017931:DNA Primers / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009154:Mutation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen / Q000627:therapeutic use; D014157:Transcription Factors / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D018931:Antineoplastic Agents, Hormonal; D058534:Class I Phosphatidylinositol 3-Kinases; D017931:DNA Primers; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen; D014157:Transcription Factors; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human; C494918:AKT1 protein, human