Aop:167

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Status

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

https://aopwiki.org/aops/167


AOP Title

Early-life estrogen receptor activity leading to endometrial carcinoma in the mouse.
Short name: Early onset ER activity and endometrial carcinoma

Authors

Cancer AOP Workgroup. National Health and Environmental Effects Research Laboratory, Office of Research and Development, Integrated Systems Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC. Corresponding author for wiki entry (wood.charles@epa.gov)

Status

Please follow the link to snapshots page to view and create Snapshots of this AOP.

Under development: Do not distribute or cite.

OECD Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA Toxcast high throughput screening data for hazard identification

This AOP page was last modified on 12/11/2016.

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Abstract

This putative adverse outcome pathway (AOP) outlines potential key events leading to a tumor outcome in standard carcinogenicity models. This information is based largely on modes of action described previously in cited literature sources and is intended as a resource template for AOP development and data organization. Presentation in this Wiki does not indicate EPA acceptance of a particular pathway for a given reference agent, only that the information has been proposed in some manner. In addition, this putative AOP relates to the model species indicated and does not directly address issues of human relevance.

Background (optional)

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
Estrogen receptor (ER) activity, prepubertal increase Strong

Key Events

Event Support for Essentiality
estrogen receptor alpha, Activation Strong
SIX-1 postive basal-type progenitor cells, Promotion Strong
aberrant basal cells, Proliferation/Clonal Expansion Strong
aberrant basal cells, squamous metaplasia Strong
Hyperplasia (glandular epithelial cells of endometrium), Increased Strong

Adverse Outcome

Adverse Outcome
adenosquamous carcinomas of endometrium, Increased

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Estrogen receptor (ER) activity, prepubertal increase Directly Leads to estrogen receptor alpha, Activation Strong
estrogen receptor alpha, Activation Indirectly Leads to SIX-1 postive basal-type progenitor cells, Promotion Strong
SIX-1 postive basal-type progenitor cells, Promotion Directly Leads to aberrant basal cells, Proliferation/Clonal Expansion Strong
aberrant basal cells, Proliferation/Clonal Expansion Directly Leads to aberrant basal cells, squamous metaplasia Strong
aberrant basal cells, squamous metaplasia Directly Leads to Hyperplasia (glandular epithelial cells of endometrium), Increased Strong
Hyperplasia (glandular epithelial cells of endometrium), Increased Indirectly Leads to adenosquamous carcinomas of endometrium, Increased Strong

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Life Stage Applicability

Life Stage Evidence Links
Fetal to Parturition Moderate
Juvenile Moderate

Taxonomic Applicability

Name Scientific Name Evidence Links
mouse Mus musculus Strong NCBI

Sex Applicability

Sex Evidence Links
Female Strong

Graphical Representation

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Overall Assessment of the AOP

Domain of Applicability

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
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Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Weight of Evidence Summary

Summary Table
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Quantitative Considerations

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Considerations for Potential Applications of the AOP (optional)

References

1. Klaunig, J. E., Babich, M. A., Baetcke, K. P., Cook, J. C., Corton, J. C., David, R. M., DeLuca, J. G., Lai, D. Y., McKee, R. H., Peters, J. M., Roberts, R. A., and Fenner-Crisp, P. A. (2003). PPARalpha agonist-induced rodent tumors: modes of action and human relevance. Critical reviews in toxicology 33(6), 655-780, 10.1080/713608372.

2. Newbold, R. R., Banks, E. P., Bullock, B., and Jefferson, W. N. (2001). Uterine adenocarcinoma in mice treated neonatally with genistein. Cancer research 61(11), 4325-8.

3. Suen, A. A., Jefferson, W. N., Wood, C. E., Padilla-Banks, E., Bae-Jump, V. L., and Williams, C. J. (2016). SIX1 Oncoprotein as a Biomarker in a Model of Hormonal Carcinogenesis and in Human Endometrial Cancer. Molecular cancer research : MCR doi: 10.1158/1541-7786.MCR-16-0084, 10.1158/1541-7786.MCR-16-0084.