Aop: 200

Title

A descriptive title which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Estrogen receptor activation leading to breast cancer

Short name
A short name should also be provided that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
ER activation to breast cancer

Graphical Representation

A graphical summary of the AOP listing all the KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs should be provided. This is easily achieved using the standard box and arrow AOP diagram (see this page for example). The graphical summary is prepared and uploaded by the user (templates are available) and is often included as part of the proposal when AOP development projects are submitted to the OECD AOP Development Workplan. The graphical representation or AOP diagram provides a useful and concise overview of the KEs that are included in the AOP, and the sequence in which they are linked together. This can aid both the process of development, as well as review and use of the AOP (for more information please see page 19 of the Users' Handbook).If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Choose File’ under the “Graphical Representation” heading, which is part of the Summary of the AOP section, to select the file that you have just edited. Files must be in jpeg, jpg, gif, png, or bmp format. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading. To remove a graphical representation file, click 'Remove' and then click 'OK.'  Your graphic should no longer be displayed on the AOP page. If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you.  Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Be sure to save the diagram as jpeg, jpg, gif, png, or bmp format. Once the diagram is edited to its final state, upload the image file as described above. More help

Authors

List the name and affiliation information of the individual(s)/organisation(s) that created/developed the AOP. In the context of the OECD AOP Development Workplan, this would typically be the individuals and organisation that submitted an AOP development proposal to the EAGMST. Significant contributors to the AOP should also be listed. A corresponding author with contact information may be provided here. This author does not need an account on the AOP-KB and can be distinct from the point of contact below. The list of authors will be included in any snapshot made from an AOP. More help

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

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

Point of Contact

Indicate the point of contact for the AOP-KB entry itself. This person is responsible for managing the AOP entry in the AOP-KB and controls write access to the page by defining the contributors as described below. Clicking on the name will allow any wiki user to correspond with the point of contact via the email address associated with their user profile in the AOP-KB. This person can be the same as the corresponding author listed in the authors section but isn’t required to be. In cases where the individuals are different, the corresponding author would be the appropriate person to contact for scientific issues whereas the point of contact would be the appropriate person to contact about technical issues with the AOP-KB entry itself. Corresponding authors and the point of contact are encouraged to monitor comments on their AOPs and develop or coordinate responses as appropriate.  More help
Brendan Ferreri-Hanberry   (email point of contact)

Contributors

List user names of all  authors contributing to or revising pages in the AOP-KB that are linked to the AOP description. This information is mainly used to control write access to the AOP page and is controlled by the Point of Contact.  More help
  • Molly M Morgan
  • Brendan Ferreri-Hanberry

Status

The status section is used to provide AOP-KB users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. “Author Status” is an author defined field that is designated by selecting one of several options from a drop-down menu (Table 3). The “Author Status” field should be changed by the point of contact, as appropriate, as AOP development proceeds. See page 22 of the User Handbook for definitions of selection options. More help
Author status OECD status OECD project SAAOP status
Open for adoption Under Development
This AOP was last modified on April 05, 2021 18:16
The date the AOP was last modified is automatically tracked by the AOP-KB. The date modified field can be used to evaluate how actively the page is under development and how recently the version within the AOP-Wiki has been updated compared to any snapshots that were generated. More help

Revision dates for related pages

Page Revision Date/Time
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
N/A, Mitochondrial dysfunction 1 March 12, 2018 11:19
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 May 08, 2019 14:14
Increase, DNA damage May 08, 2019 12:28
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 March 06, 2019 10:03
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 May 08, 2019 15:09
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

In the abstract section, authors should provide a concise and informative summation of the AOP under development that can stand-alone from the AOP page. Abstracts should typically be 200-400 words in length (similar to an abstract for a journal article). Suggested content for the abstract includes the following: The background/purpose for initiation of the AOP’s development (if there was a specific intent) A brief description of the MIE, AO, and/or major KEs that define the pathway A short summation of the overall WoE supporting the AOP and identification of major knowledge gaps (if any) If a brief statement about how the AOP may be applied (optional). The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance More help

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)

This optional subsection 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. Examples of potential uses of the optional background section are listed on pages 24-25 of the User Handbook. More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a stressor and the biological system) of an AOP. More help
Key Events (KE)
This table summarises all of the KEs of the AOP. This table is populated in the AOP-Wiki as KEs are added to the AOP. Each table entry acts as a link to the individual KE description page.  More help
Adverse Outcomes (AO)
An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP.  More help
Sequence Type Event ID Title Short name
1 MIE 1181 Activation, Estrogen receptor Activation, Estrogen receptor
2 KE 1182 Increase, Cell Proliferation (Epithelial Cells) Increase, Cell Proliferation (Epithelial Cells)
3 KE 1183 Decreased, Apoptosis (Epithelial Cells) Decreased, Apoptosis (Epithelial Cells)
4 KE 177 N/A, Mitochondrial dysfunction 1 N/A, Mitochondrial dysfunction 1
5 KE 1088 Increased, Oxidative Stress Increased, Oxidative Stress
6 KE 1187 Increased, ER binding to DNA (classical pathway) Increased, ER binding to DNA (classical pathway)
7 KE 1188 Increased, ER binding to T.F. to DNA (non-classical pathway) Increased, ER binding to T.F. to DNA (non-classical pathway)
8 KE 1189 Increased, Proliferation (Endothelial cells) Increased, Proliferation (Endothelial cells)
9 KE 1190 Increased, Migration (Endothelial Cells) Increased, Migration (Endothelial Cells)
10 KE 1191 Increased, Non-genomic signaling Increased, Non-genomic signaling
11 KE 1192 Increased, Ductal Hyperplasia Increased, Ductal Hyperplasia
12 KE 1194 Increase, DNA damage Increase, DNA Damage
13 KE 1195 modulation, Extracellular Matrix Composition modulation, Extracellular Matrix Composition
14 KE 1196 Increased, Invasion Increased, Invasion
15 KE 1197 Activation, Fibroblasts Activation, Fibroblasts
16 KE 1198 Activation, Macrophages Activation, Macrophages
17 KE 1213 Increased, Angiogenesis Increased, Angiogenesis
18 KE 1239 Altered, Gene Expression Altered, Gene Expression
19 KE 1240 Altered, Protein Production Altered, Protein Production
20 KE 1241 Increased, Motility Increased, Motility
21 KE 1242 Increased, Second Messenger Production Increased, Second Messenger Production
22 AO 1193 N/A, Breast Cancer N/A, Breast Cancer

Relationships Between Two Key Events (Including MIEs and AOs)

TESTINGThis table summarises all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP. Each table entry acts as a link to the individual KER description page.To add a key event relationship click on either Add relationship: events adjacent in sequence or Add relationship: events non-adjacent in sequence.For example, if the intended sequence of KEs for the AOP is [KE1 > KE2 > KE3 > KE4]; relationships between KE1 and KE2; KE2 and KE3; and KE3 and KE4 would be defined using the add relationship: events adjacent in sequence button.  Relationships between KE1 and KE3; KE2 and KE4; or KE1 and KE4, for example, should be created using the add relationship: events non-adjacent button. This helps to both organize the table with regard to which KERs define the main sequence of KEs and those that provide additional supporting evidence and aids computational analysis of AOP networks, where non-adjacent KERs can result in artifacts (see Villeneuve et al. 2018; DOI: 10.1002/etc.4124).After clicking either option, the user will be brought to a new page entitled ‘Add Relationship to AOP.’ To create a new relationship, select an upstream event and a downstream event from the drop down menus. The KER will automatically be designated as either adjacent or non-adjacent depending on the button selected. The fields “Evidence” and “Quantitative understanding” can be selected from the drop-down options at the time of creation of the relationship, or can be added later. See the Users Handbook, page 52 (Assess Evidence Supporting All KERs for guiding questions, etc.).  Click ‘Create [adjacent/non-adjacent] relationship.’  The new relationship should be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. To edit a key event relationship, click ‘Edit’ next to the name of the relationship you wish to edit. The user will be directed to an Editing Relationship page where they can edit the Evidence, and Quantitative Understanding fields using the drop down menus. Once finished editing, click ‘Update [adjacent/non-adjacent] relationship’ to update these fields and return to the AOP page.To remove a key event relationship to an AOP page, under Summary of the AOP, next to “Relationships Between Two Key Events (Including MIEs and AOs)” click ‘Remove’ The relationship should no longer be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. More help
Title Adjacency Evidence Quantitative Understanding
Activation, Estrogen receptor leads to Increased, ER binding to DNA (classical pathway) adjacent High High
Increase, Cell Proliferation (Epithelial Cells) leads to Increased, Ductal Hyperplasia adjacent High High
Decreased, Apoptosis (Epithelial Cells) leads to Increased, Ductal Hyperplasia adjacent High High
Activation, Estrogen receptor leads to Increased, ER binding to T.F. to DNA (non-classical pathway) adjacent High High
Increased, ER binding to DNA (classical pathway) leads to Increase, Cell Proliferation (Epithelial Cells) adjacent High High
Increased, ER binding to T.F. to DNA (non-classical pathway) leads to Increase, Cell Proliferation (Epithelial Cells) adjacent High High
Increased, Ductal Hyperplasia leads to N/A, Breast Cancer adjacent High High
Increased, Proliferation (Endothelial cells) leads to Increased, Angiogenesis adjacent High High
Increased, Migration (Endothelial Cells) leads to Increased, Angiogenesis adjacent High High
Activation, Estrogen receptor leads to Increased, Non-genomic signaling adjacent Moderate High
Increased, Non-genomic signaling leads to Increased, ER binding to T.F. to DNA (non-classical pathway) adjacent High High
Increased, ER binding to DNA (classical pathway) leads to Altered, Gene Expression adjacent High High
Increased, ER binding to T.F. to DNA (non-classical pathway) leads to Altered, Gene Expression adjacent High High
Altered, Gene Expression leads to Altered, Protein Production adjacent High High
Altered, Protein Production leads to Increased, Oxidative Stress adjacent High High
Increased, Oxidative Stress leads to Increase, DNA Damage adjacent High High
Increase, DNA Damage leads to Altered, Gene Expression adjacent High High
Increased, Non-genomic signaling leads to Altered, Gene Expression adjacent High High
Altered, Protein Production leads to Increased, Proliferation (Endothelial cells) adjacent High High
Altered, Protein Production leads to Decreased, Apoptosis (Epithelial Cells) adjacent High High
Altered, Protein Production leads to Increased, Motility adjacent Moderate Moderate
Increased, Motility leads to Increased, Invasion adjacent Moderate Moderate
Activation, Estrogen receptor leads to Increased, Second Messenger Production adjacent Moderate Moderate
Increased, Second Messenger Production leads to Increased, Non-genomic signaling adjacent Moderate Moderate

Network View

The AOP-Wiki automatically generates a network view of the AOP. This network graphic is based on the information provided in the MIE, KEs, AO, KERs and WoE summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Stressors

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. 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. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help

Life Stage Applicability

Identify the life stage for which the KE is known to be applicable. More help
Life stage Evidence
Not Otherwise Specified High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
cat Felis catus High NCBI
dog Canis lupus familiaris High NCBI

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Sex Evidence
Unspecific High

Overall Assessment of the AOP

This section addresses the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and WoE for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). The goal of the overall assessment is to provide a high level synthesis and overview of the relative confidence in the AOP and where the significant gaps or weaknesses are (if they exist). Users or readers can drill down into the finer details captured in the KE and KER descriptions, and/or associated summary tables, as appropriate to their needs.Assessment of the AOP is organised into a number of steps. Guidance on pages 59-62 of the User Handbook is available to facilitate assignment of categories of high, moderate, or low confidence for each consideration. While it is not necessary to repeat lengthy text that appears elsewhere in the AOP description (or related KE and KER descriptions), a brief explanation or rationale for the selection of high, moderate, or low confidence should be made. More help

Domain of Applicability

The relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Biological domain of applicability is informed by the “Description” and “Biological Domain of Applicability” sections of each KE and KER description (see sections 2G and 3E for details). In essence the taxa/life-stage/sex applicability is defined based on the groups of organisms for which the measurements represented by the KEs can feasibly be measured and the functional and regulatory relationships represented by the KERs are operative.The relevant biological domain of applicability of the AOP as a whole will nearly always be defined based on the most narrowly restricted of its KEs and KERs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the biological domain of applicability of the AOP as a whole would be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE and KER descriptions, the rationale for defining the relevant biological domain of applicability of the overall AOP should be briefly summarised on the AOP page. More help

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

An important aspect of assessing an AOP is evaluating the essentiality of its KEs. The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence.The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs.When assembling the support for essentiality of the KEs, authors should organise relevant data in a tabular format. The objective is to summarise briefly the nature and numbers of investigations in which the essentiality of KEs has been experimentally explored either directly or indirectly. See pages 50-51 in the User Handbook for further definitions and clarifications.  More help

Evidence Assessment

The biological plausibility, empirical support, and quantitative understanding from each KER in an AOP are assessed together.  Biological plausibility of each of the KERs in the AOP is the most influential consideration in assessing WoE or degree of confidence in an overall hypothesised AOP for potential regulatory application (Meek et al., 2014; 2014a). Empirical support entails consideration of experimental data in terms of the associations between KEs – namely dose-response concordance and temporal relationships between and across multiple KEs. It is examined most often in studies of dose-response/incidence and temporal relationships for stressors that impact the pathway. While less influential than biological plausibility of the KERs and essentiality of the KEs, empirical support can increase confidence in the relationships included in an AOP. For clarification on how to rate the given empirical support for a KER, as well as examples, see pages 53- 55 of the User Handbook.  More help

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 Understanding

Some proof of concept examples to address the WoE considerations for AOPs quantitatively have recently been developed, based on the rank ordering of the relevant Bradford Hill considerations (i.e., biological plausibility, essentiality and empirical support) (Becker et al., 2017; Becker et al, 2015; Collier et al., 2016). Suggested quantitation of the various elements is expert derived, without collective consideration currently of appropriate reporting templates or formal expert engagement. Though not essential, developers may wish to assign comparative quantitative values to the extent of the supporting data based on the three critical Bradford Hill considerations for AOPs, as a basis to contribute to collective experience.Specific attention is also given to how precisely and accurately one can potentially predict an impact on KEdownstream based on some measurement of KEupstream. This is captured in the form of quantitative understanding calls for each KER. See pages 55-56 of the User Handbook for a review of quantitative understanding for KER's. More help

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.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 or 'Update and continue' to continue editing AOP text sections.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page. More help

References

List the bibliographic references to original papers, books or other documents used to support the AOP. More help

Aboussekhra, A. (2011). Role of cancer-associated fibroblasts in breast cancer development and prognosis. Int J Dev Biol, 55(7-9), 841-849. Albini, A., Graf, J., Kitten, G. T., Kleinman, H. K., Martin, G. R., Veillette, A., et al. (1986). 17 beta-estradiol regulates and v-Ha-ras transfection constitutively enhances MCF7 breast cancer cell interactions with basement membrane. Proc Natl Acad Sci U S A, 83(21), 8182-8186. Applanat, M. P., Buteau-Lozano, H., Herve, M. A., & Corpet, A. (2008). Vascular endothelial growth factor is a target gene for estrogen receptor and contributes to breast cancer progression. Adv Exp Med Biol, 617, 437-444. Bailey, S. T., Shin, H., Westerling, T., Liu, X. S., & Brown, M. (2012). Estrogen receptor prevents p53-dependent apoptosis in breast cancer. Proc Natl Acad Sci U S A, 109(44), 18060-18065. Bjornstrom, L., & Sjoberg, M. (2005). Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol, 19(4), 833-842. Bohrer, L. R., & Schwertfeger, K. L. (2012). Macrophages promote fibroblast growth factor receptor-driven tumor cell migration and invasion in a Cxcr2-dependent manner. Mol Cancer Res, 10(10), 1294-1305. Bourdeau, V., Deschenes, J., Metivier, R., Nagai, Y., Nguyen, D., Bretschneider, N., et al. (2004). Genome-wide identification of high-affinity estrogen response elements in human and mouse. Mol Endocrinol, 18(6), 1411-1427. Bracke, M. E., Charlier, C., Bruyneel, E. A., Labit, C., Mareel, M. M., & Castronovo, V. (1994). Tamoxifen restores the E-cadherin function in human breast cancer MCF-7/6 cells and suppresses their invasive phenotype. Cancer Res, 54(17), 4607-4609. Bulun, S. E., Lin, Z., Zhao, H., Lu, M., Amin, S., Reierstad, S., et al. (2009). Regulation of aromatase expression in breast cancer tissue. Ann N Y Acad Sci, 1155, 121-131. Caldon, C. E. (2014). Estrogen Signaling and the DNA Damage Response in Hormone Dependent Breast Cancers. Front Oncol, 4. Calippe, B., Douin-Echinard, V., Delpy, L., Laffargue, M., Lelu, K., Krust, A., et al. (2010). 17Beta-estradiol promotes TLR4-triggered proinflammatory mediator production through direct estrogen receptor alpha signaling in macrophages in vivo. J Immunol, 185(2), 1169-1176. Campbell, L., Emmerson, E., Williams, H., Saville, C. R., Krust, A., Chambon, P., et al. (2014). Estrogen receptor-alpha promotes alternative macrophage activation during cutaneous repair. J Invest Dermatol, 134(9), 2447-2457. Cavalieri, E., Frenkel, K., Liehr, J. G., Rogan, E., & Roy, D. (2000). Estrogens as endogenous genotoxic agents--DNA adducts and mutations. J Natl Cancer Inst Monogr(27), 75-93. Ciocca, D. R., & Fanelli, M. A. (1997). Estrogen receptors and cell proliferation in breast cancer. Trends Endocrinol Metab, 8(8), 313-321. Dabrosin, C., Margetts, P. J., & Gauldie, J. (2003). Estradiol increases extracellular levels of vascular endothelial growth factor in vivo in murine mammary cancer. Int J Cancer, 107(4), 535-540. Dabrosin, C., Palmer, K., Muller, W. J., & Gauldie, J. (2003). Estradiol promotes growth and angiogenesis in polyoma middle T transgenic mouse mammary tumor explants. Breast Cancer Res Treat, 78(1), 1-6. Demirpence, E., Duchesne, M. J., Badia, E., Gagne, D., & Pons, M. (1993). MVLN cells: a bioluminescent MCE-7-derived cell line to study the modulation of estrogenic activity. J Steroid Biochem Mol Biol, 46(3), 355-364. Dirat, B., Bochet, L., Dabek, M., Daviaud, D., Dauvillier, S., Majed, B., et al. (2011). Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res, 71(7), 2455-2465. Doisneau-Sixou, S. F., Sergio, C. M., Carroll, J. S., Hui, R., Musgrove, E. A., & Sutherland, R. L. (2003). Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells. Endocr Relat Cancer, 10(2), 179-186. Felty, Q., & Roy, D. (2005). Estrogen, mitochondria, and growth of cancer and non-cancer cells. [Review]. Journal of Carcinogenesis, 4(1), 1. Felty, Q., Singh, K. P., & Roy, D. (2005). Estrogen-induced G1|[sol]|S transition of G0-arrested estrogen-dependent breast cancer cells is regulated by mitochondrial oxidant signaling. Oncogene, 24(31), 4883-4893. Hall, J. M., Couse, J. F., & Korach, K. S. (2001). The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem, 276(40), 36869-36872. Haslam, S. Z., & Woodward, T. L. (2003). Host microenvironment in breast cancer development: Epithelial-cell–stromal-cell interactions and steroid hormone action in normal and cancerous mammary gland. [Review]. Breast Cancer Research, 5(4), 208. Hayashi, S. I., Eguchi, H., Tanimoto, K., Yoshida, T., Omoto, Y., Inoue, A., et al. (2003). The expression and function of estrogen receptor alpha and beta in human breast cancer and its clinical application. Endocr Relat Cancer, 10(2), 193-202. Improta-Brears, T., Whorton, A. R., Codazzi, F., York, J. D., Meyer, T., & McDonnell, D. P. (1999). Estrogen-induced activation of mitogen-activated protein kinase requires mobilization of intracellular calcium. Proc Natl Acad Sci U S A, 96(8), 4686-4691. Ioachim, E., Charchanti, A., Briasoulis, E., Karavasilis, V., Tsanou, H., Arvanitis, D. L., et al. (2002). Immunohistochemical expression of extracellular matrix components tenascin, fibronectin, collagen type IV and laminin in breast cancer: their prognostic value and role in tumour invasion and progression. Eur J Cancer, 38(18), 2362-2370. Lee, A. V., Jackson, J. G., Gooch, J. L., Hilsenbeck, S. G., Coronado-Heinsohn, E., Osborne, C. K., et al. (1999). Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo. Mol Endocrinol, 13(5), 787-796. Lu, P., Weaver, V. M., & Werb, Z. (2012). The extracellular matrix: A dynamic niche in cancer progression. J Cell Bio, 196(4). Mao, Y., Keller, E. T., Garfield, D. H., Shen, K., & Wang, J. (2013). Stroma Cells in Tumor Microenvironment and Breast Cancer. Cancer Metastasis Rev, 32(0), 303-315. Marchese, S., & Silva, E. (2012). Disruption of 3D MCF-12A breast cell cultures by estrogens--an in vitro model for ER-mediated changes indicative of hormonal carcinogenesis. PLoS One, 7(10), e45767. McDonnell, D. P., & Norris, J. D. (2002). Connections and regulation of the human estrogen receptor. Science, 296(5573), 1642-1644. Mobley, J. A., & Brueggemeier, R. W. (2004). Estrogen receptor-mediated regulation of oxidative stress and DNA damage in breast cancer. Carcinogenesis, 25(1), 3-9. Mor, G., Yue, W., Santen, R. J., Gutierrez, L., Eliza, M., Berstein, L. M., et al. (1998). Macrophages, estrogen and the microenvironment of breast cancer. J Steroid Biochem Mol Biol, 67(5-6), 403-411. Morgan, M. M., Johnson, B. P., Livingston, M. K., Schuler, L. A., Alarid, E. T., Sung, K. E., et al. (2016). Personalized in vitro cancer models to predict therapeutic response: Challenges and a framework for improvement. Pharmacol Ther. Musgrove, E. A., & Sutherland, R. L. (2009). Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer, 9(9), 631-643. Novaro, V., Roskelley, C. D., & Bissell, M. J. (2003). Collagen-IV and laminin-1 regulate estrogen receptor α expression and function in mouse mammary epithelial cells. J Cell Sci, 116(Pt 14), 2975-2986. O'Lone, R., Frith, M. C., Karlsson, E. K., & Hansen, U. (2004). Genomic targets of nuclear estrogen receptors. Mol Endocrinol, 18(8), 1859-1875. Obeid, E., Nanda, R., Fu, Y. X., & Olopade, O. I. (2013). The role of tumor-associated macrophages in breast cancer progression Int J Oncol (Vol. 43, pp. 5-12). OECD. (2012). Proposal for a template and guidance on developing and assessing the completeness of adverse outcome pathways: OECD. Paoletti, C., Muniz, M. C., Thomas, D. G., Griffith, K. A., Kidwell, K. M., Tokudome, N., et al. (2015). Development of circulating tumor cell-endocrine therapy index in patients with hormone receptor-positive breast cancer. Clin Cancer Res, 21(11), 2487-2498. Platet, N., Cathiard, A. M., Gleizes, M., & Garcia, M. (2004). Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion. Crit Rev Oncol Hematol, 51(1), 55-67. Provenzano, P. P., Eliceiri, K. W., Campbell, J. M., Inman, D. R., White, J. G., & Keely, P. J. (2006). Collagen reorganization at the tumor-stromal interface facilitates local invasion. [Research article]. BMC Medicine, 4(1), 38. Provenzano, P. P., Inman, D. R., Eliceiri, K. W., Knittel, J. G., Yan, L., Rueden, C. T., et al. (2008). Collagen density promotes mammary tumor initiation and progression. [Research article]. BMC Medicine, 6(1), 11. Saji, S., Kawakami, M., Hayashi, S., Yoshida, N., Hirose, M., Horiguchi, S., et al. (2005). Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer. Oncogene, 24(28), 4531-4539. Santen, R. J., Santner, S. J., Pauley, R. J., Tait, L., Kaseta, J., Demers, L. M., et al. (1997). Estrogen production via the aromatase enzyme in breast carcinoma: which cell type is responsible? J Steroid Biochem Mol Biol, 61(3-6), 267-271. Sastre-Serra, J., Nadal-Serrano, M., Pons, D. G., Roca, P., & Oliver, J. (2012). Mitochondrial dynamics is affected by 17beta-estradiol in the MCF-7 breast cancer cell line. Effects on fusion and fission related genes. Int J Biochem Cell Biol, 44(11), 1901-1905. Sastre-Serra, J., Nadal-Serrano, M., Pons, D. G., Valle, A., Oliver, J., & Roca, P. (2015). The Effects of 17β-estradiol on Mitochondrial Biogenesis and Function in Breast Cancer Cell Lines are Dependent on the ERα/ERβ Ratio. Cellular Physiology and Biochemistry, 29(1-2), 261-268. Sastre-Serra, J., Valle, A., Company, M. M., Garau, I., Oliver, J., & Roca, P. (2010). Estrogen down-regulates uncoupling proteins and increases oxidative stress in breast cancer. Free Radic Biol Med, 48(4), 506-512. Sengupta, K., Banerjee, S., Saxena, N., & Banerjee, S. K. (2003). Estradiol-induced vascular endothelial growth factor-A expression in breast tumor cells is biphasic and regulated by estrogen receptor-alpha dependent pathway. Int J Oncol, 22(3), 609-614. Simoncini, T., Mannella, P., Fornari, L., Caruso, A., Varone, G., & Genazzani, A. R. (2004). Genomic and non-genomic effects of estrogens on endothelial cells. Steroids, 69(8-9), 537-542. Simpson, E. R. (2003). Sources of estrogen and their importance. J Steroid Biochem Mol Biol, 86(3-5), 225-230. Soon, P. S., Kim, E., Pon, C. K., Gill, A. J., Moore, K., Spillane, A. J., et al. (2013). Breast cancer-associated fibroblasts induce epithelial-to-mesenchymal transition in breast cancer cells. Endocr Relat Cancer, 20(1), 1-12. Sounni, N. E., & Noel, A. (2013). Targeting the tumor microenvironment for cancer therapy. Clin Chem, 59(1), 85-93. Tan, J., Buache, E., Chenard, M. P., Dali-Youcef, N., & Rio, M. C. (2011). Adipocyte is a non-trivial, dynamic partner of breast cancer cells. Int J Dev Biol, 55(7-9), 851-859. Thompson, E. W., Reich, R., Shima, T. B., Albini, A., Graf, J., Martin, G. R., et al. (1988). Differential regulation of growth and invasiveness of MCF-7 breast cancer cells by antiestrogens. Cancer Res, 48(23), 6764-6768. van Landeghem, A. A., Poortman, J., Nabuurs, M., & Thijssen, J. H. (1985). Endogenous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue. Cancer Res, 45(6), 2900-2906. Wang, T. T., & Phang, J. M. (1995). Effects of estrogen on apoptotic pathways in human breast cancer cell line MCF-7. Cancer Res, 55(12), 2487-2489. Williams, J. A., & Phillips, D. H. (2000). Mammary expression of xenobiotic metabolizing enzymes and their potential role in breast cancer. Cancer Res, 60(17), 4667-4677. Yager, J. D., & Davidson, N. E. (2006). Estrogen carcinogenesis in breast cancer. N Engl J Med, 354(3), 270-282. Yamaguchi, Y. (2007). Microenvironmental regulation of estrogen signals in breast cancer. Breast Cancer, 14(2), 175-181. Yamamoto, M., Hosoda, M., Nakano, K., Jia, S., Hatanaka, K. C., Takakuwa, E., et al. (2014). p53 accumulation is a strong predictor of recurrence in estrogen receptor-positive breast cancer patients treated with aromatase inhibitors. Cancer Sci, 105(1), 81-88. Zhang, X. H., Giuliano, M., Trivedi, M. V., Schiff, R., & Osborne, C. K. (2013). Metastasis dormancy in estrogen receptor-positive breast cancer. Clin Cancer Res, 19(23), 6389-6397. Zheng, S., Huang, J., Zhou, K., Zhang, C., Xiang, Q., Tan, Z., et al. (2011). 17β-Estradiol Enhances Breast Cancer Cell Motility and Invasion via Extra-Nuclear Activation of Actin-Binding Protein Ezrin PLoS One (Vol. 6). Zivadinovic, D., Gametchu, B., & Watson, C. S. (2004). Membrane estrogen receptor-α levels in MCF-7 breast cancer cells predict cAMP and proliferation responses. [Research article]. Breast Cancer Research, 7(1).