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Relationship: 3627

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Promotion, SIX1 positive progenitor cells in endometrium leads to Increase, Hyperplasia (glandular epithelial cells of endometrium)

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Promotion, SIX1 positive progenitor cells in endometrium
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Increase, Hyperplasia (glandular epithelial cells of endometrium)

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Early-life estrogen receptor agonism leading to endometrial adenosquamous carcinoma via promotion of sine oculis homeobox 1 progenitor cells adjacent High Moderate Travis Karschnik (send email) Under Development: Contributions and Comments Welcome

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
Mus musculus Mus musculus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Female High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Embryo High
Adult High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Due to the pressure applied by six1 expression on cell proliferation and progenitor population expansion, the early developmental establishment of six1+ progenitor cells in the endometrium allows for subseqent altered differentiation, including hyperplasia.

Suen et al., 2016 and Jefferson et al., 2011 both observed distinct cell-type specific six1 transcript expression differences.  “In the vaginal and cervical epithelium, SIX1 localized to the stratified squamous epithelium, with highest expression in the basal and suprabasal layers. In the endocervix, nuclear SIX1 immunolabeling was observed in simple columnar glandular epithelial cells only when there was a layer of progenitor-like basal cells directly subjacent to the luminal cells. SIX1 expression was not observed in endometrial luminal epithelium or morphologically normal glands.  SIX1 protein localized within abnormal basal cells and all atypical hyperplastic and neoplastic lesions." (Suen et al., 2016).  

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

This Key Event Relationship was part of an Environmental Protection Agency effort to develop AOPs that establish scientifically supported causal linkages between alternative endpoints measured using new approach methodologies (NAMs) and guideline apical endpoints measured in Tier 1 and Tier 2 test guidelines (U.S. EPA, 2024) employed by the Endocrine Disruptor Screening Program (EDSP).  A series of key events that represent significant, measurable, milestones connecting molecular initiation to apical endpoints indicative of adversity were identified based on scientific review articles and empirical studies.  Additionally, scientific evidence supporting the causal relationships between each pair of key events was assembled and evaluated.  The present effort focused primarily on empirical studies with laboratory rodents and other mammals.

A set of related publications, Suen et al., 2016, and 2018 were used as originating publications followed by further investigation of the bibliography and google scholar to retrieve full articles. 

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Dysregulated six1 expression promotes progenitor expansion and plasticity.  Importantly, six1 expression is not normally seen in the endometrial epithelium.  However, under the influence of neonatal estrogen treatments, established six1+ progenitor cells do occur.  Subsequent expansion of undifferentiated or poorly committed cells can predispose to aberrant differentiations pathways, including hyperplastic changes.

Suen et al., 2019 showed evidence that >90% of the Differentially Expressed Genes (DEGs) in cell division, nuclear division, and mitosis, were down regulated in Six1(deleted) vs. Six1+/+ mice. Nine of the top ten down regulated genes from these GO categories encoded either spindle associated proteins (Spag5, Kif18b, Ska3, Mis18bp1, Ska1, Aurbk, Ercc6l) or cell394 cycle regulators (Ccnb1 and Ccna2). This is consistent with the well-established role of SIX1 in regulating cell proliferation and potentially resulting in increased hyperplasia.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Suen et al., 2016 measured uteri from GEN and DES exposed mice at 5 days, and 6, 12, and 18 months after treatment.  They found no evidence of basal cell, squamous metaplasia, or other proliferative lesions until the observations at 6 months, which continued prominently at 12 and 18 months as well.  Notably, both basal cell and squamous metaplasia were prominent features of atypical hyperplasias and carcinomas in GEN or DES exposed mice.

Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Taxonomic Applicability

The evidence presented here derive from mouse tissues.  The taxonomic applicability could plausibly be extended to other mammals expressing the six1 protein and having a uterus.measured.

Lifestage Applicability

The evidence pres eneted here were made during postnatal day 1 through 18 months.  The lifestage applicability is relevent to the early developmental stages, where estrogenic influences come into play, and subsequent development to adulthood where the effects are measured.

Sex Applicability

The sex applicability is limited to females as a consequence of the measurement occuring on endometrial tissue. 

References

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

Suen, A. A., Jefferson, W. N., Williams, C. J., & Wood, C. E. (2018). Differentiation patterns of uterine carcinomas and precursor lesions induced by neonatal estrogen exposure in mice. Toxicologic pathology, 46(5), 574-596.

Suen, A. A., Jefferson, W. N., Wood, C. E., Padilla-Banks, E., Bae-Jump, V. L., & Williams, C. J. (2016). SIX1 oncoprotein as a biomarker in a model of hormonal carcinogenesis and in human endometrial cancer. Molecular Cancer Research, 14(9), 849-858.

Suen, A. A., Jefferson, W. N., Wood, C. E., & Williams, C. J. (2019). SIX1 regulates aberrant endometrial epithelial cell differentiation and cancer latency following developmental estrogenic chemical exposure. Molecular Cancer Research, 17(12), 2369-2382.