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AOP: 503

Title

A descriptive phrase 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

Activation of uterine estrogen receptor-alfa leading to endometrial adenocarcinoma, via epigenetic modulation

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

Activation of uterine estrogen receptor-alfa, endometrial adenocarcinoma

The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help

Handbook Version v2.6

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help

Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Barbara Viviani, Università degli Studi di Milano, Milan, Italy

Elena Bernardini, Università degli Studi di Milano, Milan, Italy

Valentina Galbiati, Università degli Studi di Milano, Milan, Italy

Ambra Maddalon, Università degli Studi di Milano, Milan, Italy

Gloria Melzi, Università degli Studi di Milano, Milan, Italy

Miriam Midali, Università degli Studi di Milano, Milan, Italy

Melania Serafini, Università degli Studi di Milano, Milan, Italy

Emanuela Corsini, Università degli Studi di Milano, Milan, Italy

Roberto Cosimo Melcangi, Università degli Studi di Milano, Milan, Italy

Eugenio Scanziani, Università degli Studi di Milano, Milan, Italy

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section. More help

Barbara Viviani (email point of contact)

Contributors

Users with write access to the AOP page. Entries in this field are controlled by the Point of Contact. More help

Barbara Viviani
Miriam Midali

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication. More help

OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version
1.100	Under Review

This AOP was last modified on February 20, 2025 11:02

Revision dates for related pages

Page	Revision Date/Time
Activation, estrogen receptor alpha	November 21, 2024 17:42
Epigenetic modification process	November 10, 2024 06:09
Expression of factors ruling proliferation, modified	January 03, 2025 11:09
Increase, Hyperplasia (glandular epithelial cells of endometrium)	January 03, 2025 11:25
Genomic instability	January 03, 2025 11:58
Uterine adenocarcinoma (endometrioid adenocarcinoma Type I)	March 06, 2025 08:39
Activation, estrogen receptor alpha leads to Epigenetic modification process	March 27, 2025 06:04
Epigenetic modification process leads to Expression of factors ruling proliferation, modified	March 27, 2025 06:50
Expression of factors ruling proliferation, modified leads to Increase, Hyperplasia (glandular epithelial cells of endometrium)	March 27, 2025 07:00
Increase, Hyperplasia (glandular epithelial cells of endometrium) leads to Genomic instability	March 27, 2025 07:05
Genomic instability leads to endometrioid adenocarcinoma Type I	March 27, 2025 07:12
Tamoxifen	November 29, 2016 18:42
17beta-Estradiol	November 29, 2016 18:42

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

This AOP describes the links between activation of the uterine estrogen receptor alpha and endometrial adenocarcinoma via epigenetic modulation. An evidence-based approach methodology was adopted for this specific purpose. Uterine (endometrial) adenocarcinoma (UA), the most common type of uterine cancer, is a cancer that arises in the layer of cells that make up the inner epithelial lining of the uterus (endometrium). Based on clinical, pathological and molecular characteristics, human uterine adenocarcinomas have been divided into two broad categories: type I and type II. The Molecular Initiating Event (MIE) in this AOP is the activation of the uterine estrogen receptor alpha (ERα). ERα is a receptor covalently bound by estrogens, which upon dimerisation can translocate to the nucleus where it can bind to estrogen-responsive elements and recruit co-activators or co-repressors, which can attract co-regulatory proteins. The mayor KEs are an epigenetic modification process (KE1), the modification of expression of factors ruling proliferation (KE2), than hyperplasia of glandular epithelial cells of endometrium (KE3), than a genomic instability (KE4) than lead to uterine adenocarcinoma (AO).

The outcome is intended to support the identification of substances with endocrine disrupting properties. For this specific purpose, an evidence-based approach methodology was used. The available evidence from the literature was systematically mapped to identify MIEs and KEs associated with AO, independent of prototypical stressors, by means of:

1. a priori defined search strategies initially addressing the AO and biologically plausible MIEs,

2. application of machine learning technique (Topic modelling) that automatically analyzes text data to identify biologically plausible KERs,

3. systematic literature review and critical appraisal of prioritized evidence, taking into account human, in vivo and in vitro studies.

Estradiol and tamoxifen, two recognised human risk factors for endometrioid adenocarcinoma, were used as tool chemicals to empirically support the response and temporal concordance of the identified Key Event Relationships (KERs). All evidence was then integrated using the AOP conceptual network.

AOP Development Strategy

Context

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. More help

Uterine (endometrial) adenocarcinoma (UA), the most common uterine cancer, is a type of cancer that arises in the layer of cells that form the inner epithelial lining of the uterus (endometrium). Based on clinical, pathological and molecular features, uterine adenocarcinomas in humans have been classified into two broad categories: type I and type II (Sherman, 2000).

Type I adenocarcinoma is the most common type, accounting for approximately 80% of cases. It is often referred as endometrioid adenocarcinoma since it is a well differentiated (low grade) tumor characterized by a glandular growth pattern resembling normal endometrial epithelium. Clinically, is often characterized by a favorable prognosis. Type I adenocarcinoma is estrogen-dependent, estrogen-receptor-positive and arises in a background of endometrial hyperplasia. It can be polypoid or infiltrative, the latter can spread transmurally through the uterine wall and to adjacent organs. Involvement of regional lymph nodes can occur and, in advanced stages, the tumor may metastasize to distant organs including lungs, liver, bones, and other organs (Robbins and Cotran, 2015).

Type II adenocarcinoma comprises about 10-20% of UA cases and has a non-endometrioid morphology. It is non-estrogen-dependent, estrogen-receptor-negative and has a serous, papillary, or clear cell morphology (Sherman, 2000). Clinically, it is characterized by an aggressive clinical course, and a propensity for early spread and poor prognosis (Bansal et al. 2009). It arises in a background of endometrial atrophy. This classification that sub-divide uterine adenocarcinomas into types I and II is not completely accurate since a minority of endometrial cancers may exhibit shared characteristics (Bansal et al. 2009).

The dependence of Type I uterine adenocarcinoma on estrogens is supported by different epidemiologic observations:

- the raised incidence rate for uterine adenocarcinoma in the population in conjunction with widespread use of unopposed estrogen replacement therapy in menopause (Sherman 2000)

- the decreased incidence with the decline in the use of this hormone preparations (Sherman 2000)

- the increased risk of UA as a consequence of the use of oral contraceptives based on estrogens (Weiss et al. 1976; 1980)

- the 2 to 3 times increase in the relative risk of developing UA in patients under tamoxifen therapy, due to its agonistic action on estrogen receptors in endometrial tissue (Passarello et al. 2019).

Prolonged estrogenic stimulation of the endometrium is associated with atypical endometrial hyperplasia (Sherman 2000). Endometrial hyperplasia is characterized by an increased (pathological) proliferation of the endometrial epithelial cells compared with normal proliferative endometrium.

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components. Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

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Events:

Molecular Initiating Events (MIE)

An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help

Key Events (KE)

A measurable event within a specific biological level of organisation. More help

Adverse Outcomes (AO)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

MIE

1065

Activation, estrogen receptor alpha

KE	2152	Epigenetic modification process	Epigenetic modification process
KE	2153	Expression of factors ruling proliferation, modified	Expression of factors ruling proliferation, modified
KE	772	Increase, Hyperplasia (glandular epithelial cells of endometrium)	Increase, Hyperplasia (glandular epithelial cells of endometrium)
KE	1896	Genomic instability	Genomic instability

2154

Uterine adenocarcinoma (endometrioid adenocarcinoma Type I)

endometrioid adenocarcinoma Type I

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes 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. More help

Title	Adjacency	Evidence	Quantitative Understanding

Activation, estrogen receptor alpha leads to Epigenetic modification process	adjacent
Epigenetic modification process leads to Expression of factors ruling proliferation, modified	adjacent
Expression of factors ruling proliferation, modified leads to Increase, Hyperplasia (glandular epithelial cells of endometrium)	adjacent
Increase, Hyperplasia (glandular epithelial cells of endometrium) leads to Genomic instability	adjacent
Genomic instability leads to endometrioid adenocarcinoma Type I	adjacent

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (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

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Name
Tamoxifen
17beta-Estradiol

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Life stage	Evidence
Adult

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. More help

Term	Scientific Term	Evidence	Link
human	Homo sapiens		NCBI
mouse	Mus musculus		NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Sex	Evidence
Female

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

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. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Modulating Factor (MF)	Influence or Outcome	KER(s) involved

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

Considerations for Potential Applications of the AOP (optional)

Addressess 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. More help

References

List of the literature that was cited for this AOP. More help

Sherman ME (2000). Theories of endometrial carcinogenesis: a multidisciplinary approach. Mod Pathol., 13, 295–308

Robbins and Cotran (2015) Pathologic basis of disease. 9 th Edition.

Bansal N, Yendluri V, and Wenham RM, 2009. The Molecular Biology of Endometrial Cancers and the Implications for Pathogenesis, Classification, and Targeted Therapies. Cancer Control, Vol. 16, No. 1

Weiss NS, Sayvetz TA. Incidence of endometrial cancer in relation to the use of oral contraceptives. N Engl J Med. 1980 Mar 6;302(10):551-4. doi: 10.1056/NEJM198003063021004

Passarello K, Kurian S.,Villanueva V. (2019) Endometrial cancer: an overview of pathophysiology, management and care. Sem. Oncol. Nurs., 35, 157-165

Weiss,N.S., Szekely,D.R. and Austin,D.F. (1976) Increasing incidence of endometrial cancer in the United States. N. Engl. J. Med., 294, 1259–1262