Format

Send to

Choose Destination
Mol Syst Biol. 2016 Mar 10;12(3):860. doi: 10.15252/msb.20156506.

Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility.

Author information

1
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA Division of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA Department of Biology, Brigham Young University, Provo, UT, USA.
2
Huntsman Cancer Institute, Salt Lake City, UT, USA Department of Biology, University of Utah, Salt Lake City, UT, USA.
3
Huntsman Cancer Institute, Salt Lake City, UT, USA.
4
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA.
5
Huntsman Cancer Institute, Salt Lake City, UT, USA Department of Medicine, University of Utah, Salt Lake City, UT, USA.
6
Department of Surgery, Duke University School of Medicine, Durham, NC, USA.
7
Department of Surgery, University of Utah, Salt Lake City, UT, USA.
8
Huntsman Cancer Institute, Salt Lake City, UT, USA Department of Biology, University of Utah, Salt Lake City, UT, USA Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA.
9
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
10
Division of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA.
11
Division of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA.
12
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA andreab@genetics.utah.edu.

Abstract

The signaling events that drive familial breast cancer (FBC) risk remain poorly understood. While the majority of genomic studies have focused on genetic risk variants, known risk variants account for at most 30% of FBC cases. Considering that multiple genes may influence FBC risk, we hypothesized that a pathway-based strategy examining different data types from multiple tissues could elucidate the biological basis for FBC. In this study, we performed integrated analyses of gene expression and exome-sequencing data from peripheral blood mononuclear cells and showed that cell adhesion pathways are significantly and consistently dysregulated in women who develop FBC. The dysregulation of cell adhesion pathways in high-risk women was also identified by pathway-based profiling applied to normal breast tissue data from two independent cohorts. The results of our genomic analyses were validated in normal primary mammary epithelial cells from high-risk and control women, using cell-based functional assays, drug-response assays, fluorescence microscopy, and Western blotting assays. Both genomic and cell-based experiments indicate that cell-cell and cell-extracellular matrix adhesion processes seem to be disrupted in non-malignant cells of women at high risk for FBC and suggest a potential role for these processes in FBC development.

KEYWORDS:

breast cancer; cellular adhesion; disease susceptibility; multiomic analysis, signaling pathways

PMID:
26969729
PMCID:
PMC4812528
DOI:
10.15252/msb.20156506
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center