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Aop: 167

AOP Title

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Early-life estrogen receptor activity leading to endometrial carcinoma in the mouse.

Short name:

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Early onset ER activity and endometrial carcinoma

Graphical Representation

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Click to download graphical representation template

Authors

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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)

Point of Contact

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Charles Wood   (email point of contact)

Contributors

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  • Charles Wood

Status

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Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite 1.29 Under Development


This AOP was last modified on January 27, 2018 15:34

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Revision dates for related pages

Page Revision Date/Time
prepubertal increase, Estrogen receptor (ER) activity December 03, 2016 16:37
Activation, estrogen receptor alpha December 03, 2016 16:37
Promotion, SIX-1 postive basal-type progenitor cells September 16, 2017 10:17
Proliferation/Clonal Expansion, aberrant basal cells September 16, 2017 10:17
squamous metaplasia, aberrant basal cells December 03, 2016 16:37
Increased, Hyperplasia (glandular epithelial cells of endometrium) September 16, 2017 10:17
Increased, adenosquamous carcinomas of endometrium September 16, 2017 10:17
prepubertal increase, Estrogen receptor (ER) activity leads to Activation, estrogen receptor alpha December 03, 2016 16:38
Activation, estrogen receptor alpha leads to Promotion, SIX-1 postive basal-type progenitor cells December 03, 2016 16:38
Promotion, SIX-1 postive basal-type progenitor cells leads to Proliferation/Clonal Expansion, aberrant basal cells December 03, 2016 16:38
Proliferation/Clonal Expansion, aberrant basal cells leads to squamous metaplasia, aberrant basal cells December 03, 2016 16:38
squamous metaplasia, aberrant basal cells leads to Increased, Hyperplasia (glandular epithelial cells of endometrium) December 03, 2016 16:38
Increased, Hyperplasia (glandular epithelial cells of endometrium) leads to Increased, adenosquamous carcinomas of endometrium December 03, 2016 16:38
Diethylstilbestrol November 29, 2016 18:42
Genistein November 29, 2016 18:42

Abstract

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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)

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Summary of the AOP

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Events: Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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Sequence Type Event ID Title Short name
1 MIE 1064 prepubertal increase, Estrogen receptor (ER) activity prepubertal increase, Estrogen receptor (ER) activity
2 KE 1065 Activation, estrogen receptor alpha Activation, estrogen receptor alpha
3 KE 1066 Promotion, SIX-1 postive basal-type progenitor cells Promotion, SIX-1 postive basal-type progenitor cells
4 KE 1067 Proliferation/Clonal Expansion, aberrant basal cells Proliferation/Clonal Expansion, aberrant basal cells
5 KE 1068 squamous metaplasia, aberrant basal cells squamous metaplasia, aberrant basal cells
6 KE 1069 Increased, Hyperplasia (glandular epithelial cells of endometrium) Increased, Hyperplasia (glandular epithelial cells of endometrium)
7 AO 1070 Increased, adenosquamous carcinomas of endometrium Increased, adenosquamous carcinomas of endometrium

Relationships Between Two Key Events
(Including MIEs and AOs)

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Title Adjacency Evidence Quantitative Understanding
prepubertal increase, Estrogen receptor (ER) activity leads to Activation, estrogen receptor alpha adjacent High
Promotion, SIX-1 postive basal-type progenitor cells leads to Proliferation/Clonal Expansion, aberrant basal cells adjacent High
Proliferation/Clonal Expansion, aberrant basal cells leads to squamous metaplasia, aberrant basal cells adjacent High
squamous metaplasia, aberrant basal cells leads to Increased, Hyperplasia (glandular epithelial cells of endometrium) adjacent High
Activation, estrogen receptor alpha leads to Promotion, SIX-1 postive basal-type progenitor cells non-adjacent High
Increased, Hyperplasia (glandular epithelial cells of endometrium) leads to Increased, adenosquamous carcinomas of endometrium non-adjacent High

Network View

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Stressors

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Name Evidence Term
Diethylstilbestrol
Genistein

Life Stage Applicability

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Life stage Evidence
Fetal to Parturition Moderate
Juvenile Moderate

Taxonomic Applicability

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Term Scientific Term Evidence Link
mouse Mus musculus High NCBI

Sex Applicability

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Sex Evidence
Female High

Overall Assessment of the AOP

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Domain of Applicability

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Essentiality of the Key Events

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Evidence Assessment

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Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

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References

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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.