TY - JOUR
T1 - Protein pathway activation mapping of brain metastasis from lung and breast cancers reveals organ type specific drug target activation
AU - Improta, Giuseppina
AU - Zupa, Angela
AU - Fillmore, Helen
AU - Deng, Jianghong
AU - Aieta, Michele
AU - Musto, Pellegrino
AU - Liotta, Lance A.
AU - Broaddus, William
AU - Petricoin, Emanuel F.
AU - Wulfkuhle, Julia D.
PY - 2011/7/1
Y1 - 2011/7/1
N2 - Brain metastases are the most common fatal complication of systemic cancer, especially of lung (40-50%) and breast (20-30%) cancers. In this era of personalized therapy, there is a critical need to uncover the signaling architecture of brain metastases; however, little is known about what signaling pathways are activated in the context of the brain microenvironment. Using a unique study set of 42 brain metastases from patients with breast or nonsmall cell lung cancer (NSCLC), the phosphorylation/activation states of 128 key signaling proteins involved in cancer signaling were measured in laser capture microdissected tumor epithelium using reverse phase protein microarray (RPMA) technology. Distinct pathway activation subgroups from both breast and lung metastases were underpinned by, among others, ERBB2, AKT, mTOR, EGFR, SMAD, and ERK-p38 signaling. Breast cancer metastases showed significantly (p < 0.05) higher activation of the c-ERBB2/IGFR-AKT pathway network compared to NSCLC metastases, whereas NSCLC metastases to the brain exhibited higher relative levels of many members of the EGFR-ERK signaling network. Protein pathway activation mapping using RPMA revealed both the heterogeneity of signaling networks in brain metastases that would require a prior stratification to targeted therapies as well as the requirement of direct analysis of the metastatic lesion.
AB - Brain metastases are the most common fatal complication of systemic cancer, especially of lung (40-50%) and breast (20-30%) cancers. In this era of personalized therapy, there is a critical need to uncover the signaling architecture of brain metastases; however, little is known about what signaling pathways are activated in the context of the brain microenvironment. Using a unique study set of 42 brain metastases from patients with breast or nonsmall cell lung cancer (NSCLC), the phosphorylation/activation states of 128 key signaling proteins involved in cancer signaling were measured in laser capture microdissected tumor epithelium using reverse phase protein microarray (RPMA) technology. Distinct pathway activation subgroups from both breast and lung metastases were underpinned by, among others, ERBB2, AKT, mTOR, EGFR, SMAD, and ERK-p38 signaling. Breast cancer metastases showed significantly (p < 0.05) higher activation of the c-ERBB2/IGFR-AKT pathway network compared to NSCLC metastases, whereas NSCLC metastases to the brain exhibited higher relative levels of many members of the EGFR-ERK signaling network. Protein pathway activation mapping using RPMA revealed both the heterogeneity of signaling networks in brain metastases that would require a prior stratification to targeted therapies as well as the requirement of direct analysis of the metastatic lesion.
UR - http://www.scopus.com/inward/record.url?scp=79959966646&partnerID=8YFLogxK
U2 - 10.1021/pr200065t
DO - 10.1021/pr200065t
M3 - Article
C2 - 21574647
AN - SCOPUS:79959966646
SN - 1535-3893
VL - 10
SP - 3089
EP - 3097
JO - Journal of Proteome Research
JF - Journal of Proteome Research
IS - 7
ER -