Molly M. Morgan, Brian P. Johnson, David J. Beebe
Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison
Point of Contact
Molly M Morgan
- Molly M Morgan
|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 Do not cite||Under Development|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
|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|
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.
This optional section should be used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development. The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. Instructions To add background information, click Edit in the upper right hand menu on the AOP page. Under the “Background (optional)” field, a text editable form provides ability to edit the Background. Clicking ‘Update AOP’ will update these fields.
Summary of the AOP
StressorsDescribes stressors known to trigger the MIE and provides evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. The evidence supporting the stressor will typically consist of a brief description and citation of literature showing that particular stressors can trigger the MIE. Instructions To add a stressor associated with an AOP, under “Summary of the AOP” click ‘Add Stressor’ will bring user to the “New Aop Stressor” page. In the Name field, user can search for stressor by name. Choosing a stressor from the resulting drop down populates the field. Selection of an Evidence level from the drop down menu and add any supporting evidence in the text box. Click ‘Add stressor’ to add the stressor to the AOP page.
Molecular Initiating Event
|Activation, Estrogen receptor||Activation, Estrogen receptor|
|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|
|N/A, Breast Cancer||N/A, Breast Cancer|
Relationships Between Two Key Events (Including MIEs and AOs)
Life Stage Applicability
|Not Otherwise Specified||Strong|
|dog||Canis lupus familiaris||Strong||NCBI|
Graphical RepresentationClick to download graphical representation template
Overall Assessment of the AOP
This section addresses the relevant domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and weight of evidence for the overall hypothesised AOP (i.e., including the MIE, KEs and AO) as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). It draws upon the evidence assembled for each KER as one of several components which contribute to relative confidence in supporting information for the entire hypothesised pathway. An important component in assessing confidence in supporting information as a basis to consider regulatory application of AOPs beyond that described in Section 6 is the essentiality of each of the key events as a component of the entire pathway. This is normally investigated in specifically-designed stop/reversibility studies or knockout models (i.e., those where a key event can be blocked or prevented). Assessment of the overall AOP also contributes to the identification of KEs for which confidence in the quantitative relationship with the AO is greatest (i.e., to facilitate determining the most sensitive predictor of the AO). Instructions To edit the “Overall Assessment of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Overall Assessment of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page. The new text should appear under the “Overall Assessment of the AOP” section on the AOP page.
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 EventsThe essentiality of various of the KEs is influential in considering confidence in an overall hypothesised AOP for potential regulatory application being secondary only to biological plausibility of KERs (Meek et al., 2014; 2014a). The defining question for determining essentiality (included in Annex 1) relates to whether or not downstream KEs and/or the AO is prevented if an upstream event is experimentally blocked. It is assessed, generally, then, on the basis of direct experimental evidence of the absence/reduction of downstream KEs when an upstream KE is blocked or diminished (e.g., in null animal models or reversibility studies). Weight of evidence for essentiality of KEs would be considered high if there is direct evidence from specifically designed experimental studies illustrating essentiality for at least one of the important key events [e.g., stop/reversibility studies, antagonism, knock out models, etc.) moderate if there is indirect 25 evidence that experimentally induced change of an expected modulating factor attenuates or augments a key event (e.g., augmentation of proliferative response (KEupstream) leading to increase in tumour formation (KEdownstream or AO)) and weak if there is no or contradictory experimental evidence of the essentiality of any of the KEs (Annex 1). Instructions To edit the “Essentiality of the Key Events” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Essentiality of the Key Events” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page. The new text should appear under the “Essentiality of the Key Events” section on the AOP page.
Weight of Evidence Summary
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 ConsiderationsThe extent of quantitative understanding of the various KERs in the overall hypothesised AOP is also critical in consideration of potential regulatory application. For some applications (e.g. doseresponse analysis in in depth risk assessment), quantitative characterisation of downstream KERs may be essential while for others, quantitative understanding of upstream KERs may be important (e.g., QSAR modelling for category formation for testing). Because evidence that contributes to quantitative understanding of the KER is generally not mutually exclusive with the empirical support for the KER, evidence that contributes to quantitative understanding should generally be considered as part of the evaluation of the weight of evidence supporting the KER (see Annex 1, footnote b). General guidance on the degree of quantitative understanding that would be characterised as weak, moderate, or strong is provided in Annex 2. Instructions To edit the “Quantitative Considerations” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Quantitative Considerations” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page. The new text should appear under the “Quantitative Considerations” section on the AOP page.
Considerations for Potential Applications of the AOP (optional)
At their discretion, the developer may include in this section discussion of the potential applications of an AOP to support regulatory decision-making. This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale. Detailing such considerations can aid the process of transforming narrative descriptions of AOPs into practical tools. In this context, it is necessarily beneficial to involve members of the regulatory risk assessment community on the development and assessment team. The Network view which is generated based on assessment of weight of evidence/degree of confidence in the hypothesized AOP taking into account the elements described in Section 7 provides a useful summary of relevant information as a basis to consider appropriate application in a regulatory context. Consideration of application needs then, to take into consideration the following rank ordered qualitative elements: Confidence in biological plausibility for each of the KERs Confidence in essentiality of the KEs Empirical support for each of the KERs and overall AOP The extent of weight of evidence/confidence in both these qualitative elements and that of the quantitative understanding for each of the KERs (e.g., is the MIE known, is quantitative understanding restricted to early or late key events) is also critical in determining appropriate application. For example, if the confidence and quantitative understanding of each KER in a hypothesised AOP are low and or low/moderate and the evidence for essentiality of KEs weak (Section 7), it might be considered as appropriate only for applications with less potential for impact (e.g., prioritisation, category formation for testing) versus those that have immediate implications potentially for risk management (e.g., in depth assessment). If confidence in quantitative understanding of late key events is high, this might be sufficient for an in depth assessment. The analysis supporting the Network view is also essential in identifying critical data gaps based on envisaged regulatory application. Instructions To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page. The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page.
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