Keywords
breast cancer, cellular adhesion, disease susceptibility, multiomic analysis, signaling pathways
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.
Original Publication Citation
Piccolo SR, Hoffman LM, Conner T, Shrestha G, Cohen AL, Marks JR, Neumayer LA, Agarwal CA, Beckerle MC, Andrulis IL, Spira AE, Moos PJ, Buys SS, Johnson WE, Bild AH. Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility. Molecular Systems Biology, 2016 Mar; 12(3): 860
BYU ScholarsArchive Citation
Piccolo, Stephen R.; Hoffman, Laura M.; Conner, Thomas; Shrestha, Gajendra; Cohen, Adam L.; Marks, Jeffrey R.; Neumayer, Leigh A.; Agarwal, Cori A.; Beckerle, Mary C.; Andrulis, Irene L.; Spira, Avrum E.; Moos, Philip J.; Buys, Saundra S.; Johnson, William Evan; and Bild, Andrea H., "Integrative Analyses Reveal Signaling Pathways Underlying Familial Breast Cancer Susceptibility" (2016). Faculty Publications. 7461.
https://scholarsarchive.byu.edu/facpub/7461
Document Type
Peer-Reviewed Article
Publication Date
2016-03-11
Publisher
EMBO Press
Language
English
College
Life Sciences
Department
Biology
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