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AOP: 200
Title
Estrogen receptor activation leading to breast cancer
Short name
Graphical Representation
Point of Contact
Contributors
- Molly M Morgan
Coaches
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
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This AOP was last modified on July 04, 2024 09:50
Revision dates for related pages
Page | Revision Date/Time |
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Activation, Estrogen receptor | September 16, 2017 10:17 |
Increase, Cell Proliferation (Epithelial Cells) | May 08, 2019 12:41 |
Decreased, Apoptosis (Epithelial Cells) | September 16, 2017 10:17 |
Mitochondrial dysfunction | April 17, 2024 08:26 |
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) | February 29, 2024 04:42 |
Increased, Non-genomic signaling | September 16, 2017 10:17 |
Increased, Ductal Hyperplasia | September 16, 2017 10:17 |
N/A, Breast Cancer | February 29, 2024 08:48 |
Increase, DNA damage | May 08, 2019 12:28 |
modulation, Extracellular Matrix Composition | September 16, 2017 10:17 |
Increased, Invasion | February 29, 2024 05:03 |
Activation, Fibroblasts | September 16, 2017 10:17 |
Activation, Macrophages | September 16, 2017 10:17 |
Increased, Angiogenesis | December 20, 2022 09:08 |
Altered, Gene Expression | March 06, 2019 10:03 |
Altered, Protein Production | September 16, 2017 10:17 |
Increased, Motility | February 28, 2024 10:31 |
Increased, Second Messenger Production | September 16, 2017 10:17 |
Oxidative Stress | August 26, 2024 10:26 |
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 | May 08, 2019 15:09 |
Increased, Proliferation (Endothelial cells) leads to Increased, Angiogenesis | December 20, 2022 09:28 |
Increased, Migration (Endothelial Cells) leads to Increased, Angiogenesis | December 20, 2022 09:29 |
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 Oxidative Stress | July 04, 2024 09:39 |
Oxidative Stress leads to Increase, DNA Damage | July 04, 2024 09:39 |
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 | February 29, 2024 09:39 |
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
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.
AOP Development Strategy
Context
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
---|
MIE | 1181 | Activation, Estrogen receptor | Activation, Estrogen receptor |
KE | 1182 | Increase, Cell Proliferation (Epithelial Cells) | Increase, Cell Proliferation (Epithelial Cells) |
KE | 1183 | Decreased, Apoptosis (Epithelial Cells) | Decreased, Apoptosis (Epithelial Cells) |
KE | 177 | Mitochondrial dysfunction | Mitochondrial dysfunction |
KE | 1392 | Oxidative Stress | Oxidative Stress |
KE | 1187 | Increased, ER binding to DNA (classical pathway) | Increased, ER binding to DNA (classical pathway) |
KE | 1188 | Increased, ER binding to T.F. to DNA (non-classical pathway) | Increased, ER binding to T.F. to DNA (non-classical pathway) |
KE | 1189 | Increased, Proliferation (Endothelial cells) | Increased, Proliferation (Endothelial cells) |
KE | 1190 | Increased, Migration (Endothelial Cells) | Increased, Migration (Endothelial Cells) |
KE | 1191 | Increased, Non-genomic signaling | Increased, Non-genomic signaling |
KE | 1192 | Increased, Ductal Hyperplasia | Increased, Ductal Hyperplasia |
KE | 1194 | Increase, DNA damage | Increase, DNA Damage |
KE | 1195 | modulation, Extracellular Matrix Composition | modulation, Extracellular Matrix Composition |
KE | 1196 | Increased, Invasion | Increased, Invasion |
KE | 1197 | Activation, Fibroblasts | Activation, Fibroblasts |
KE | 1198 | Activation, Macrophages | Activation, Macrophages |
KE | 1213 | Increased, Angiogenesis | Increased, Angiogenesis |
KE | 1239 | Altered, Gene Expression | Altered, Gene Expression |
KE | 1240 | Altered, Protein Production | Altered, Protein Production |
KE | 1241 | Increased, Motility | Increased, Motility |
KE | 1242 | Increased, Second Messenger Production | Increased, Second Messenger Production |
AO | 1193 | N/A, Breast Cancer | N/A, Breast Cancer |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
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Network View
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
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Not Otherwise Specified | High |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Unspecific | High |
Overall Assessment of the AOP
Domain of Applicability
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
Evidence Assessment
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.
Known Modulating Factors
Quantitative Understanding
Considerations for Potential Applications of the AOP (optional)
References
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