Protein pathway activation mapping of brain metastasis from lung and breast cancers reveals organ type specific drug target activation

Giuseppina Improta, Angela Zupa, Helen Fillmore, Jianghong Deng, Michele Aieta, Pellegrino Musto, Lance A. Liotta, William Broaddus, Emanuel F. Petricoin, Julia D. Wulfkuhle

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)3089-3097
Number of pages9
JournalJournal of Proteome Research
Volume10
Issue number7
DOIs
Publication statusPublished - Jul 1 2011

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)

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