title: Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility.
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.
authors.affiliation: 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.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Piccolo
authors.affiliation: Huntsman Cancer Institute, Salt Lake City, UT, USA Department of Biology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Hoffman
authors.affiliation: Huntsman Cancer Institute, Salt Lake City, UT, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Conner
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Gajendra
authors.initials: G
authors.lastname: Shrestha
authors.affiliation: Huntsman Cancer Institute, Salt Lake City, UT, USA Department of Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Cohen
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Marks
authors.affiliation: Department of Surgery, University of Utah, Salt Lake City, UT, USA.
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Neumayer
authors.affiliation: Department of Surgery, University of Utah, Salt Lake City, UT, USA.
authors.forename: Cori A
authors.initials: CA
authors.lastname: Agarwal
authors.affiliation: 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.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Beckerle
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Andrulis
authors.affiliation: Division of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Avrum E
authors.initials: AE
authors.lastname: Spira
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Moos
authors.affiliation: Huntsman Cancer Institute, Salt Lake City, UT, USA Department of Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Saundra S
authors.initials: SS
authors.lastname: Buys
authors.affiliation: Division of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA.
authors.forename: William Evan
authors.initials: WE
authors.lastname: Johnson
authors.affiliation: 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.
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Bild
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008875:Middle Aged; D015398:Signal Transduction
keywords: breast cancer; cellular adhesion; disease susceptibility; multiomic analysis, signaling pathways