Anita Muthukaruppan
Multimodal assessment of estrogen receptor mRNA profiles to quantify estrogen pathway activity in breast tumors
Muthukaruppan, Anita; Lasham, Annette; Woad, Kathryn J.; Black, Michael A.; Blenkiron, Cherie; Miller, Lance D.; Harris, Gavin; McCarthy, Nicole; Findlay, Michael P.; Shelling, Andrew N.; Print, Cristin G.
Authors
Annette Lasham
KATIE WOAD katie.woad@nottingham.ac.uk
Assistant Professor
Michael A. Black
Cherie Blenkiron
Lance D. Miller
Gavin Harris
Nicole McCarthy
Michael P. Findlay
Andrew N. Shelling
Cristin G. Print
Abstract
Background
Molecular markers have transformed our understanding of the heterogeneity of breast cancer and have allowed the identification of genomic profiles of estrogen receptor (ER)-α signaling. However, our understanding of the transcriptional profiles of ER signaling remains inadequate. Therefore, we sought to identify the genomic indicators of ER pathway activity that could supplement traditional immunohistochemical (IHC) assessments of ER status to better understand ER signaling in the breast tumors of individual patients.
Materials and Methods
We reduced ESR1 (gene encoding the ER-α protein) mRNA levels using small interfering RNA in ER+ MCF7 breast cancer cells and assayed for transcriptional changes using Affymetrix HG U133 Plus 2.0 arrays. We also compared 1034 ER+ and ER− breast tumors from publicly available microarray data. The principal components of ER activity generated from these analyses and from other published estrogen signatures were compared with ESR1 expression, ER-α IHC, and patient survival.
Results
Genes differentially expressed in both analyses were associated with ER-α IHC and ESR1 mRNA expression. They were also significantly enriched for estrogen-driven molecular pathways associated with ESR1, cyclin D1 (CCND1), MYC (v-myc avian myelocytomatosis viral oncogene homolog), and NFKB (nuclear factor kappa B). Despite their differing constituent genes, the principal components generated from these new analyses and from previously published ER-associated gene lists were all associated with each other and with the survival of patients with breast cancer treated with endocrine therapies.
Conclusion
A biomarker of ER-α pathway activity, generated using ESR1-responsive mRNAs in MCF7 cells, when used alongside ER-α IHC and ESR1 mRNA expression, could provide a method for further stratification of patients and add insight into ER pathway activity in these patients.
Citation
Muthukaruppan, A., Lasham, A., Woad, K. J., Black, M. A., Blenkiron, C., Miller, L. D., …Print, C. G. (2017). Multimodal assessment of estrogen receptor mRNA profiles to quantify estrogen pathway activity in breast tumors. Clinical Breast Cancer, 17(2), https://doi.org/10.1016/j.clbc.2016.09.001
Journal Article Type | Article |
---|---|
Acceptance Date | Sep 2, 2016 |
Online Publication Date | Sep 13, 2016 |
Publication Date | Apr 1, 2017 |
Deposit Date | Oct 20, 2016 |
Publicly Available Date | Oct 20, 2016 |
Journal | Clinical Breast Cancer |
Print ISSN | 1526-8209 |
Electronic ISSN | 1938-0666 |
Publisher | Elsevier |
Peer Reviewed | Peer Reviewed |
Volume | 17 |
Issue | 2 |
DOI | https://doi.org/10.1016/j.clbc.2016.09.001 |
Keywords | Breast cancer; ER; ESR1; Gene expression; MCF7; Principal component analysis; RNA |
Public URL | https://nottingham-repository.worktribe.com/output/970105 |
Publisher URL | http://www.sciencedirect.com/science/article/pii/S1526820916302403 |
Contract Date | Oct 20, 2016 |
Files
Muthukarappan et al 2016.pdf
(3 Mb)
PDF
Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0
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