Activity of Distinct Growth Factor Receptor Network Components in Breast Tumors Uncovers Two Biologically Relevant Subtypes

Authors

Moom Roosan, Chapman UniversityFollow
Shelley M. MacNeil, University of Utah
David F. Jenkins, Boston University
Gajendra Shrestha, University of Utah
Sydney R. Wyatt, University of Utah
Jasmine A. McQuerry, University of Utah
Stephen R. Piccolo, University of Utah
Laura M. Heiser, Oregon Health and Sciences University
Joe W. Gray, Oregon Health and Sciences University
W. Evan Johnson, University of Utah
Andrea H. Bild, University of Utah

Document Type

Article

Publication Date

4-26-2017

Abstract

Background
The growth factor receptor network (GFRN) plays a significant role in driving key oncogenic processes. However, assessment of global GFRN activity is challenging due to complex crosstalk among GFRN components, or pathways, and the inability to study complex signaling networks in patient tumors. Here, pathway-specific genomic signatures were used to interrogate GFRN activity in breast tumors and the consequent phenotypic impact of GRFN activity patterns.

Methods
Novel pathway signatures were generated in human primary mammary epithelial cells by overexpressing key genes from GFRN pathways (HER2, IGF1R, AKT1, EGFR, KRAS (G12V), RAF1, BAD). The pathway analysis toolkit Adaptive Signature Selection and InteGratioN (ASSIGN) was used to estimate pathway activity for GFRN components in 1119 breast tumors from The Cancer Genome Atlas (TCGA) and across 55 breast cancer cell lines from the Integrative Cancer Biology Program (ICBP43). These signatures were investigated for their relationship to pro- and anti-apoptotic protein expression and drug response in breast cancer cell lines.

Results
Application of these signatures to breast tumor gene expression data identified two novel discrete phenotypes characterized by concordant, aberrant activation of either the HER2, IGF1R, and AKT pathways (“the survival phenotype”) or the EGFR, KRAS (G12V), RAF1, and BAD pathways (“the growth phenotype”). These phenotypes described a significant amount of the variability in the total expression data across breast cancer tumors and characterized distinctive patterns in apoptosis evasion and drug response. The growth phenotype expressed lower levels of BIM and higher levels of MCL-1 proteins. Further, the growth phenotype was more sensitive to common chemotherapies and targeted therapies directed at EGFR and MEK. Alternatively, the survival phenotype was more sensitive to drugs inhibiting HER2, PI3K, AKT, and mTOR, but more resistant to chemotherapies.

Conclusions
Gene expression profiling revealed a bifurcation pattern in GFRN activity represented by two discrete phenotypes. These phenotypes correlate to unique mechanisms of apoptosis and drug response and have the potential of pinpointing targetable aberration(s) for more effective breast cancer treatments.

Comments

This article was originally published in Journal, volume 9, in 2017. https://doi.org/10.1186/s13073-017-0429-x

Dr. Moom Roosan was known as Mumtahena Rahman at the time of publication.

Recommended Citation

Rahman, M., MacNeil, S.M., Jenkins, D.F. et al. Activity of distinct growth factor receptor network components in breast tumors uncovers two biologically relevant subtypes. Genome Med. 2017;9:40. https://doi.org/10.1186/s13073-017-0429-x

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.