Analysis of growth factor signaling in genetically diverse breast cancer lines.

TitleAnalysis of growth factor signaling in genetically diverse breast cancer lines.
Publication TypeJournal Article
Year of Publication2014
AuthorsNiepel, M, Hafner, M, Pace, EA, Chung, M, Chai, DH, Zhou, L, Muhlich, JL, Schoeberl, B, Sorger, PK
JournalBMC Biol
Volume12
Pagination20
Date Published2014
ISSN1741-7007
KeywordsBreast Neoplasms, Cell Line, Tumor, Cluster Analysis, Dose-Response Relationship, Drug, Extracellular Signal-Regulated MAP Kinases, Female, Humans, Insulin-Like Growth Factor I, Intercellular Signaling Peptides and Proteins, Kinetics, Ligands, Phosphatidylinositol 3-Kinases, Phosphorylation, Proto-Oncogene Proteins c-akt, Receptor, erbB-2, Signal Transduction, Time Factors
Abstract

BACKGROUND: Soluble growth factors present in the microenvironment play a major role in tumor development, invasion, metastasis, and responsiveness to targeted therapies. While the biochemistry of growth factor-dependent signal transduction has been studied extensively in individual cell types, relatively little systematic data are available across genetically diverse cell lines.RESULTS: We describe a quantitative and comparative dataset focused on immediate-early signaling that regulates the AKT (AKT1/2/3) and ERK (MAPK1/3) pathways in a canonical panel of well-characterized breast cancer lines. We also provide interactive web-based tools to facilitate follow-on analysis of the data. Our findings show that breast cancers are diverse with respect to ligand sensitivity and signaling biochemistry. Surprisingly, triple negative breast cancers (TNBCs; which express low levels of ErbB2, progesterone and estrogen receptors) are the most broadly responsive to growth factors and HER2amp cancers (which overexpress ErbB2) the least. The ratio of ERK to AKT activation varies with ligand and subtype, with a systematic bias in favor of ERK in hormone receptor positive (HR+) cells. The factors that correlate with growth factor responsiveness depend on whether fold-change or absolute activity is considered the key biological variable, and they differ between ERK and AKT pathways.CONCLUSIONS: Responses to growth factors are highly diverse across breast cancer cell lines, even within the same subtype. A simple four-part heuristic suggests that diversity arises from variation in receptor abundance, an ERK/AKT bias that depends on ligand identity, a set of factors common to all receptors that varies in abundance or activity with cell line, and an "indirect negative regulation" by ErbB2. This analysis sets the stage for the development of a mechanistic and predictive model of growth factor signaling in diverse cancer lines. Interactive tools for looking up these results and downloading raw data are available at http://lincs.hms.harvard.edu/niepel-bmcbiol-2014/.

DOI10.1186/1741-7007-12-20
Alternate JournalBMC Biol.
PubMed ID24655548
PubMed Central IDPMC4234128
Grant ListU54 CA112967 / CA / NCI NIH HHS / United States
U54 HG006097 / HG / NHGRI NIH HHS / United States
U54-CA112967 / CA / NCI NIH HHS / United States
U54-HG006097 / HG / NHGRI NIH HHS / United States