Aop:200

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Status

This is a legacy representation of this AOP. Please see the current version here:

https://aopwiki.org/aops/200


AOP Title

Estrogen receptor activation leading to breast cancer
Short name: ER activation to breast cancer

Authors

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

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

Abstract

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.

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Estrogen receptor, Activation Strong

Key Events

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

Adverse Outcome

Adverse Outcome
Breast Cancer, N/A

Relationships Among Key Events and the Adverse Outcome

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

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Life Stage Applicability

Life Stage Evidence Links
Not Otherwise Specified Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
human Homo sapiens Strong NCBI
cat Felis catus Strong NCBI
dog Canis lupus familiaris Strong NCBI

Sex Applicability

Sex Evidence Links
Unspecific Strong

Graphical Representation

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Overall Assessment of the AOP

Applicability of the AOP

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

Molecular Initiating Event Summary, Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.

Weight of Evidence Summary

Summary Table
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.

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

Summary Table
Provide an overall discussion of the quantitative information available for this AOP. Support calls for the individual relationships can be included in the Key Event Relationship table above.

References

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