Identification of novel kinase targets for the treatment of estrogen receptor-negative breast cancer.
OBJECTIVE
Previous gene expression profiling studies of breast cancer have focused on the entire genome to identify genes differentially expressed between estrogen receptor (ER) alpha-positive and ER-alpha-negative cancers.


METHODS
Here, we used gene expression microarray profiling to identify a distinct kinase gene expression profile that identifies ER-negative breast tumors and subsets ER-negative breast tumors into four distinct subtypes.


RESULTS
Based on the types of kinases expressed in these clusters, we identify a cell cycle regulatory subset, a S6 kinase pathway cluster, an immunomodulatory kinase-expressing cluster, and a mitogen-activated protein kinase pathway cluster. Furthermore, we show that this specific kinase profile is validated using independent sets of human tumors and is also seen in a panel of breast cancer cell lines. Kinase expression knockdown studies show that many of these kinases are essential for the growth of ER-negative, but not ER-positive, breast cancer cell lines. Finally, survival analysis of patients with breast cancer shows that the S6 kinase pathway signature subtype of ER-negative cancers confers an extremely poor prognosis, whereas patients whose tumors express high levels of immunomodulatory kinases have a significantly better prognosis.


CONCLUSIONS
This study identifies a list of kinases that are prognostic and may serve as druggable targets for the treatment of ER-negative breast cancer.
Speers
Corey
C
Department of Molecular and Cellular Biology, Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Tsimelzon
Anna
A
Sexton
Krystal
K
Herrick
Ashley M
AM
Gutierrez
Carolina
C
Culhane
Aedin
A
Quackenbush
John
J
Hilsenbeck
Susan
S
Chang
Jenny
J
Brown
Powel
P
D001943:Breast Neoplasms / Q000145:classification / Q000378:metabolism*; D016503:Drug Delivery Systems; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D009376:Neoplasms, Hormone-Dependent; D011960:Receptors, Estrogen / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction
D011960:Receptors, Estrogen; D019893:Ribosomal Protein S6 Kinases