API

Aop: 200

AOP Title

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Estrogen receptor activation leading to breast cancer

Short name:

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ER activation to breast cancer

Authors

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Molly M. Morgan, Brian P. Johnson, David J. Beebe

Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison

Point of Contact

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Molly M Morgan

Contributors

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  • Molly M Morgan

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development


This AOP was last modified on December 02, 2016 13:59

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Revision dates for related pages

Page Revision Date/Time
Activation, Estrogen receptor September 16, 2017 10:17
Increase, Cell Proliferation (Epithelial Cells) September 16, 2017 10:17
Decreased, Apoptosis (Epithelial Cells) September 16, 2017 10:17
N/A, Mitochondrial dysfunction 1 September 16, 2017 10:14
Increased, Oxidative Stress September 16, 2017 10:16
Increased, ER binding to DNA (classical pathway) September 16, 2017 10:17
Increased, ER binding to T.F. to DNA (non-classical pathway) September 16, 2017 10:17
Increased, Proliferation (Endothelial cells) September 16, 2017 10:17
Increased, Migration (Endothelial Cells) September 16, 2017 10:17
Increased, Non-genomic signaling September 16, 2017 10:17
Increased, Ductal Hyperplasia September 16, 2017 10:17
N/A, Breast Cancer December 03, 2016 16:37
Increase, DNA damage September 16, 2017 10:17
modulation, Extracellular Matrix Composition September 16, 2017 10:17
Increased, Invasion September 16, 2017 10:17
Activation, Fibroblasts September 16, 2017 10:17
Activation, Macrophages September 16, 2017 10:17
Increased, Angiogenesis September 16, 2017 10:17
Altered, Gene Expression September 16, 2017 10:17
Altered, Protein Production September 16, 2017 10:17
Increased, Motility September 16, 2017 10:17
Increased, Second Messenger Production September 16, 2017 10:17
Activation, Estrogen receptor leads to Increased, ER binding to DNA (classical pathway) December 03, 2016 16:38
Increase, Cell Proliferation (Epithelial Cells) leads to Increased, Ductal Hyperplasia December 03, 2016 16:38
Decreased, Apoptosis (Epithelial Cells) leads to Increased, Ductal Hyperplasia December 03, 2016 16:38
Activation, Estrogen receptor leads to Increased, ER binding to T.F. to DNA (non-classical pathway) December 03, 2016 16:38
Increased, ER binding to DNA (classical pathway) leads to Increase, Cell Proliferation (Epithelial Cells) December 03, 2016 16:38
Increased, ER binding to T.F. to DNA (non-classical pathway) leads to Increase, Cell Proliferation (Epithelial Cells) December 03, 2016 16:38
Increased, Ductal Hyperplasia leads to N/A, Breast Cancer December 03, 2016 16:38
Increased, Proliferation (Endothelial cells) leads to Increased, Angiogenesis December 03, 2016 16:38
Increased, Migration (Endothelial Cells) leads to Increased, Angiogenesis December 03, 2016 16:38
Activation, Estrogen receptor leads to Increased, Non-genomic signaling December 03, 2016 16:38
Increased, Non-genomic signaling leads to Increased, ER binding to T.F. to DNA (non-classical pathway) December 03, 2016 16:38
Increased, ER binding to DNA (classical pathway) leads to Altered, Gene Expression December 03, 2016 16:38
Increased, ER binding to T.F. to DNA (non-classical pathway) leads to Altered, Gene Expression December 03, 2016 16:38
Altered, Gene Expression leads to Altered, Protein Production December 03, 2016 16:38
Altered, Protein Production leads to Increased, Oxidative Stress December 03, 2016 16:38
Increased, Oxidative Stress leads to Increase, DNA Damage December 03, 2016 16:38
Increase, DNA Damage leads to Altered, Gene Expression December 03, 2016 16:38
Increased, Non-genomic signaling leads to Altered, Gene Expression December 03, 2016 16:38
Altered, Protein Production leads to Increased, Proliferation (Endothelial cells) December 03, 2016 16:38
Altered, Protein Production leads to Decreased, Apoptosis (Epithelial Cells) December 03, 2016 16:38
Altered, Protein Production leads to Increased, Motility December 03, 2016 16:38
Increased, Motility leads to Increased, Invasion December 03, 2016 16:38
Activation, Estrogen receptor leads to Increased, Second Messenger Production December 03, 2016 16:38
Increased, Second Messenger Production leads to Increased, Non-genomic signaling December 03, 2016 16:38

Abstract

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Endocrine disrupting chemicals (EDC), particularly estrogen receptor (ER) agonists, are thought to contribute to the incidence of breast cancer. The majority (approximately 75 percent) of breast cancer cases express the estrogen receptor. Both animal and human studies strongly support that activation of the estrogen receptor stimulates breast cancer development and progression. We created the ER-mediated breast cancer AOP to frame how ER activation (the MIE) leads to breast cancer (the AO). For more information regarding the AOP, refer to the Morgan & Johnson et al. (2015) citation.

Activation of the estrogen receptor in breast epithelial cells stimulates genomic and non-genomic changes, which alters epithelial gene expression and subsequent protein production. Consequently, breast epithelial cells experience increased proliferation, decreased apoptosis, dysfunction of mitochondrial dynamics, increased DNA damage, increased cell motility, and increased oxidative stress. These cellular changes translate to a tissue level where ductal hyperplasia and cell invasion is increased.

While breast epithelial cells are the cancer cell type in ER+ adenocarcinomas, other cell types of the microenvironment interact with the AOP. For example, endothelial cells express ER and upon ER activation, undergo gene expression and protein production changes. Consequently, endothelial cell proliferation and migration is increased, leading to increased angiogenesis, which supports the proliferation of breast cancer epithelial cells. While estrogens do not target fibroblasts, adipocytes, or macrophages directly, they become activated as breast cancer progresses. It is not well understood if there is a direct relationship between estrogen signaling and stromal cell activation, however, activated cells stimulate cancer cell proliferation, influence chemical response, increase cell motility, and rearrange the extracellular matrix. Moreover, adipocytes contribute to the AOP through metabolism of testosterone to estrogen, and fibroblasts have been shown to regulate estrogen receptor regulated genes in epithelial cells. Therefore, due to how the breast microenvironment interacts with and stimulates the AOP, we have included activation of these cell types into our framework.

Overall, the ER-mediated breast cancer AOP is a useful framework that can identify both readouts and components of the breast microenvironment that are important in disease progression.


Background (optional)

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Summary of the AOP

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Stressors

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Molecular Initiating Event

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Title Short name
Activation, Estrogen receptor Activation, Estrogen receptor

Key Events

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Title Short name
Increase, Cell Proliferation (Epithelial Cells) Increase, Cell Proliferation (Epithelial Cells)
Decreased, Apoptosis (Epithelial Cells) Decreased, Apoptosis (Epithelial Cells)
N/A, Mitochondrial dysfunction 1 N/A, Mitochondrial dysfunction 1
Increased, Oxidative Stress Increased, Oxidative Stress
Increased, ER binding to DNA (classical pathway) Increased, ER binding to DNA (classical pathway)
Increased, ER binding to T.F. to DNA (non-classical pathway) Increased, ER binding to T.F. to DNA (non-classical pathway)
Increased, Proliferation (Endothelial cells) Increased, Proliferation (Endothelial cells)
Increased, Migration (Endothelial Cells) Increased, Migration (Endothelial Cells)
Increased, Non-genomic signaling Increased, Non-genomic signaling
Increased, Ductal Hyperplasia Increased, Ductal Hyperplasia
Increase, DNA damage Increase, DNA Damage
modulation, Extracellular Matrix Composition modulation, Extracellular Matrix Composition
Increased, Invasion Increased, Invasion
Activation, Fibroblasts Activation, Fibroblasts
Activation, Macrophages Activation, Macrophages
Increased, Angiogenesis Increased, Angiogenesis
Altered, Gene Expression Altered, Gene Expression
Altered, Protein Production Altered, Protein Production
Increased, Motility Increased, Motility
Increased, Second Messenger Production Increased, Second Messenger Production

Adverse Outcome

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Title Short name
N/A, Breast Cancer N/A, Breast Cancer

Relationships Between Two Key Events (Including MIEs and AOs)

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Title Directness Evidence Quantitative Understanding
Activation, Estrogen receptor leads to Increased, ER binding to DNA (classical pathway) Directly leads to Strong Strong
Increase, Cell Proliferation (Epithelial Cells) leads to Increased, Ductal Hyperplasia Directly leads to Strong Strong
Decreased, Apoptosis (Epithelial Cells) leads to Increased, Ductal Hyperplasia Directly leads to Strong Strong
Activation, Estrogen receptor leads to Increased, ER binding to T.F. to DNA (non-classical pathway) Directly leads to Strong Strong
Increased, ER binding to DNA (classical pathway) leads to Increase, Cell Proliferation (Epithelial Cells) Directly leads to Strong Strong
Increased, ER binding to T.F. to DNA (non-classical pathway) leads to Increase, Cell Proliferation (Epithelial Cells) Directly leads to Strong Strong
Increased, Ductal Hyperplasia leads to N/A, Breast Cancer Directly leads to Strong Strong
Increased, Proliferation (Endothelial cells) leads to Increased, Angiogenesis Directly leads to Strong Strong
Increased, Migration (Endothelial Cells) leads to Increased, Angiogenesis Directly leads to Strong Strong
Activation, Estrogen receptor leads to Increased, Non-genomic signaling Directly leads to Moderate Strong
Increased, Non-genomic signaling leads to Increased, ER binding to T.F. to DNA (non-classical pathway) Directly leads to Strong Strong
Increased, ER binding to DNA (classical pathway) leads to Altered, Gene Expression Directly leads to Strong Strong
Increased, ER binding to T.F. to DNA (non-classical pathway) leads to Altered, Gene Expression Directly leads to Strong Strong
Altered, Gene Expression leads to Altered, Protein Production Directly leads to Strong Strong
Altered, Protein Production leads to Increased, Oxidative Stress Directly leads to Strong Strong
Increased, Oxidative Stress leads to Increase, DNA Damage Directly leads to Strong Strong
Increase, DNA Damage leads to Altered, Gene Expression Directly leads to Strong Strong
Increased, Non-genomic signaling leads to Altered, Gene Expression Directly leads to Strong Strong
Altered, Protein Production leads to Increased, Proliferation (Endothelial cells) Directly leads to Strong Strong
Altered, Protein Production leads to Decreased, Apoptosis (Epithelial Cells) Directly leads to Strong Strong
Altered, Protein Production leads to Increased, Motility Directly leads to Moderate Moderate
Increased, Motility leads to Increased, Invasion Directly leads to Moderate Moderate
Activation, Estrogen receptor leads to Increased, Second Messenger Production Directly leads to Moderate Moderate
Increased, Second Messenger Production leads to Increased, Non-genomic signaling Directly leads to Moderate Moderate

Network View

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Life Stage Applicability

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Life stage Evidence
Not Otherwise Specified Strong

Taxonomic Applicability

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Term Scientific Term Evidence Link
human Homo sapiens Strong NCBI
cat Felis catus Strong NCBI
dog Canis lupus familiaris Strong NCBI

Sex Applicability

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Sex Evidence
Unspecific Strong

Graphical Representation

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Click to download graphical representation template

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Overall Assessment of the AOP

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Domain of Applicability

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Sex. While females have a higher incidence of breast cancer, estrogen-receptor mediated breast cancer can occur in males and females.

Life stages. Breast cancer affects adult women and men. Older adult women have a higher probability of having an ER+ breast cancer (vs. ER-) than younger adult women.

Taxonomic applicability. Breast cancer occurs naturally in humans, cats, and dogs. In vivo studies primarily study breast cancer in mice.


Essentiality of the Key Events

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Weight of Evidence Summary

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The weight of evidence for the KERs related to epithelial cells is mostly strong. The KERs between ER activation, motility, and invasion were labeled as a moderate weight of evidence due to discrepancies in the literature regarding whether ER activation decreases motility/invasion, vs. increases motility/invasion. ER activation leading to non-genomic signaling was labeled as moderate due to the limited evidence supporting this KER. For non-epithelial cell types, we labeled the KERs relationship as mostly weak. ER activation has direct effects on endothelial cells as they express ER and several studies have correlated ER activation with increased proliferation, migration, and angiogenesis. Macrophages, fibroblasts, and adipocytes are influenced by and stimulate breast cancer progression, however, the exact correlation between ER activation and these events is still unclear.

 


Quantitative Considerations

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Considerations for Potential Applications of the AOP (optional)

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References

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