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Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility
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 t...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812528/ https://www.ncbi.nlm.nih.gov/pubmed/26969729 http://dx.doi.org/10.15252/msb.20156506 |
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author | 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 Bild, Andrea H |
author_facet | 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 Bild, Andrea H |
author_sort | Piccolo, Stephen R |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4812528 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-48125282016-04-08 Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility 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 Bild, Andrea H Mol Syst Biol Articles 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. John Wiley and Sons Inc. 2016-03-11 /pmc/articles/PMC4812528/ /pubmed/26969729 http://dx.doi.org/10.15252/msb.20156506 Text en © 2016 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Articles 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 Bild, Andrea H Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility |
title | Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility |
title_full | Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility |
title_fullStr | Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility |
title_full_unstemmed | Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility |
title_short | Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility |
title_sort | integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812528/ https://www.ncbi.nlm.nih.gov/pubmed/26969729 http://dx.doi.org/10.15252/msb.20156506 |
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