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Relationship: 2971

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

Expression of factors ruling proliferation, modified leads to Increase, Hyperplasia (glandular epithelial cells of endometrium)

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Expression of factors ruling proliferation, modified
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
Activation of uterine estrogen receptor-alfa leading to endometrial adenocarcinoma, via epigenetic modulation adjacent Barbara Viviani (send email) Under development: Not open for comment. Do not cite Under Review

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

Sex Applicability

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

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages

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

Proliferation is under the control of several different factors which promote the entry of cells into cell cycle (growth factors) and/or prevent apoptosis. This KER focuses on those factors that are under epigenetic control and have been found altered in human specimens of endometrial adenocarcinoma, with a particular attention to the estrogen dependent type I.

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

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

Overexpression, gain-of-function mutation of factors promoting replication (or repressing apoptosis) and/or downregulation, loss-of-function mutation of factors repressing replication (or triggering apoptosis), promotes an uncontrolled proliferation leading to pathologic hyperplasia. Excessive or inappropriate cells/tissue stimulation by hormones cause most forms of pathologic hyperplasia. Endometrial hyperplasia is an example of pathological hormone-induced hyperplasia (Robbins and Cotran, 2015).

Overexpressed factors in human specimens derived from uterine endometrial carcinoma (protein class as reported in the Human Protein Atlas)

  • Transcription factors:

PAX2, Type I endometrial carcinoma (Wu et al. 2005, supported by Kahraman et al. 2012). Differentiation, transcription, transcription regulation (Uniprot). Is a prognostic marker in endometrial cancers: high expression is unfavorable in endometrial cancers (Human Protein Atlas database). PAX2 is also involved in different type of cancers promoting cell proliferation (Maulbecker et al. 1993, Khoubehi 2001).

KLF-1, Type I endometrial carcinoma (previously known as erythroid Kruppel-like factor- EKLF) (Wu et al. 2005). Transcription regulator (activator) of erythrocyte development (Uniprot, McConnell et al. 2010).

  • Cancer related genes

TFF3, UA type not specified (Pandey et al. 2017, supported by Bignotti et al. 2008). Involved in the maintenance and repair of intestinal mucosas, promotes the mobility of epithelial cells in healing process (Uniprot). In physiological conditions TFF3 rules transiently increases in the proliferative phase of the endometrium (Borthwick et al. 2003). Is a prognostic marker in endometrial cancer: high expression is favourable in endometrial cancer (Human Protein Atlas database). Beside endometrial tumors, TFF3 expression is increased in colorectal (Chen et al. 2019, Yusufu et al. 2019), gastric (Taniguchi et al. 2018), lung adeno- (Zhang et al. 2019) and pancreatic carcinomas (Cheng et al. 2022) and its overexpression has been correlated to the promotion of proliferation.

NMPI, UA type not specified (Zhou et al. 2014, 2018). Involved in diverse cellular processes such as ribosome biogenesis, centrosome duplication, protein chaperoning, histone assembly, cell proliferation, and regulation of tumor suppressors p53/TP53 and ARF. Negatively regulates the activation of EIF2AK2/PKR and suppresses apoptosis through inhibition of EIF2AK2/PKR autophosphorylation (Uniprot). Antagonizes the inhibitory effect of ATF5 on cell proliferation and relieves ATF5-induced G2/M blockade (Uniprot, Liu et al. 2012). In complex with MYC enhances the transcription of MYC target genes (Uniprot, Kim et al. 2015). NMPI is involved in different type of cancers promoting cell proliferation (Grisendi et al. 2006).

DHODH, UA type not specified (Dai et al. 2021). Plays a crucial role in the de novo synthesis of pyrimidine (Barnes, 1993) necessary to maintain proliferation and is overexpressed in different type of tumors (Zhou et al. 2021)

Downregulated factors in human specimens derived from uterine endometrial carcinoma (protein class as reported in the Human Protein Atlas)

  • Transcription factors:

KLF-9, UA ERa positive (Simmons et al. 2011, supported by Simmen et al. 2008, Mutter et al. 2001). Transcription regulator (Uniprot, McConnell et al. 2010).

HOPX, endometrial carcinoma type I (Yamaguchi et al. 2009). Prevents serum response factor (SRF)-dependent transcription by inhibiting SRF binding to DNA or by recruiting histone deacetylase protein preventing transcription of SRF. May act as tumor suppressor (Uniprot). It is silenced or downregulated in different tumors and has a role in the control of proliferation (Mariotto et al. 2016)

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

Wu et al. 2005  – The chosen exposure paradigm to evaluate PAX2 expression in non-tumoral cells (5mM TAM and 100nM E2 for 3h) is based on pilot experiments done to determine the optimal duration of the treatment in cancer cells. These experiments proved that about 75% of known ER target genes were covered. The lack of exposure of control cells at different time and doses of TAM or E2 hamper the possibility to evaluate whether expression of PAX2 increased at different exposure conditions in controls. These observations would be relevant to identify molecular signs distinctive of endometrial cells transformation.

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
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

References

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

Barnes T, Parry P, Hart I, Jones C, Minet M, Patterson D. Regional mapping of the gene encoding dihydroorotate dehydrogenase, an enzyme involved in UMP synthesis, electron transport, and superoxide generation, to human chromosome region 16q22. Somat Cell Mol Genet. 1993;19:405–11.

Bignotti E, Ravaggi A, Tassi RA, Calza S, Rossi E, Falchetti M, Romani C, Bandiera E, Odicino FE, Pecorelli S, Santin AD. Trefoil factor 3: a novel serum marker identified by gene expression profiling in high-grade endometrial carcinomas. Br J Cancer. 2008 Sep 2;99(5):768-73. doi: 10.1038/sj.bjc.6604546. PMID: 18682706; PMCID: PMC2528153.

Borthwick JM, Charnock-Jones DS, Tom BD, Hull ML, Teirney R, Phillips SC, Smith SK. Determination of the transcript profile of human endometrium. Mol Hum Reprod. 2003; 9:19-33

Chen RM, Chiou YS, Chong QY, Poh HM, Tan TZ, Zhang MY, Ma L, Zhu T, Pandey V, Basappa, Kumar AP, Lobie PE. Pharmacological Inhibition of TFF3 Enhances Sensitivity of CMS4 Colorectal Carcinoma to 5-Fluorouracil through Inhibition of p44/42 MAPK. Int J Mol Sci. 2019 Dec 9;20(24):6215. doi: 10.3390/ijms20246215. PMID: 31835445; PMCID: PMC6940926.

Cheng, F., Wang, X., Chiou, YS. et al. Trefoil factor 3 promotes pancreatic carcinoma progression via WNT pathway activation mediated by enhanced WNT ligand expression. Cell Death Dis 13, 265 (2022). https://doi.org/10.1038/s41419-022-04700-4

Dai M, Yang B, Chen J, Liu F, Zhou Y, Zhou Y, Xu Q, Jiang S, Zhao S, Li X, Zhou X, Yang Q, Li J, Wang Y, Zhang Z, Teng Y. Nuclear-translocation of ACLY induced by obesity-related factors enhances pyrimidine metabolism through regulating histone acetylation in endometrial cancer. Cancer Lett. 2021 Aug 10;513:36-49. doi: 10.1016/j.canlet.2021.04.024. Epub 2021 May 13. PMID: 33991616.

Kahraman K, Kiremitci S, Taskin S, Kankaya D, Sertcelik A, Ortac F. Expression pattern of PAX2 in hyperplastic and malignant endometrium. Arch Gynecol Obstet. 2012 Jul;286(1):173-8. doi: 10.1007/s00404-012-2236-3. Epub 2012 Jan 25. PMID: 22274645.

Khoubehi, B. et al. Expression of the developmental and oncogenic PAX2 gene in human prostate cancer. J. Urol. 165, 2115–-2120 (2001).

Kim JY, Cho YE, Park JH. The Nucleolar Protein GLTSCR2 Is an Upstream Negative Regulator of the Oncogenic Nucleophosmin-MYC Axis. Am J Pathol. 2015 Jul;185(7):2061-8. doi: 10.1016/j.ajpath.2015.03.016.

Liu X, Liu D, Qian D, Dai J, An Y, Jiang S, Stanley B, Yang J, Wang B, Liu X, Liu DX. Nucleophosmin (NPM1/B23) interacts with activating transcription factor 5 (ATF5) protein and promotes proteasome- and caspase-dependent ATF5 degradation in hepatocellular carcinoma cells. J Biol Chem. 2012 Jun 1;287(23):19599-609. doi: 10.1074/jbc.M112.363622.

Mariotto A., Pavlova O., Hyun-Sook Park, Huber M, Hohl D, HOPX: The Unusual Homeodomain-Containing Protein, Journal of Investigative Dermatology, Volume 136, Issue 5, 2016, Pages 905-911, ISSN 0022-202X, https://doi.org/10.1016/j.jid.2016.01.032.

Maulbecker,C.C.&Gruss,P. The oncogenic potential of Pax genes.EMBOJ. 12, 2361–-2367 (1993).

Mutter GL, Baak JP, Fitzgerald JT, Gray R, Neuberg D, Kust GA, Gentleman R, Gullans SR, Wei LJ, Wilcox M. Global expression changes of constitutive and hormonally regulated genes during endometrial neoplastic transformation. Gynecol. Oncol 2001;83:177–185

Pandey V., Zhang M., Chong Q., You M., Rushdiana Raquib A., Pandey A. K., Liu D., Liu L., Ma L., Jha S., Wu Z., Zhu T., Lobie P. E. et al Hypomethylation associated enhanced transcription of trefoil factor-3 mediates tamoxifen-stimulated oncogenicity of ER+ endometrial carcinoma cells. Oncotarget. 2017; 8: 77268-77291. Retrieved from https://www.oncotarget.com/article/20461/

Robbins, S. L. & Cotran, R. S. (2015). Robbins and Cotran pathologic basis of disease (9th ed), Kumar V., Abbas A., Aster JC editors, Philadelphia, PA: Saunders/Elsevier.

Simmen FA, Su Y, Xiao R, Zeng Z, Simmen RC. The Kruppel-like factor 9 (KLF9) network in HEC-1- A endometrial carcinoma cells suggests the carcinogenic potential of dys-regulated KLF9 expression. Reprod.Biol.Endocrinol 2008;6:41.

Simmons CD, Pabona JM, Heard ME, Friedman TM, Spataro MT, Godley AL, Simmen FA, Burnett AF, Simmen RC. Krüppel-like factor 9 loss-of-expression in human endometrial carcinoma links altered expression of growth-regulatory genes with aberrant proliferative response to estrogen. Biol Reprod. 2011 Aug;85(2):378-85. doi: 10.1095/biolreprod.110.090654. Epub 2011 May 4. PMID: 21543766; PMCID: PMC3142261.

Taniguchi Y, Kurokawa Y, Takahashi T, Mikami J, Miyazaki Y, Tanaka K, Makino T, Yamasaki M, Nakajima K, Mori M, Doki Y. Prognostic Value of Trefoil Factor 3 Expression in Patients with Gastric Cancer. World J Surg. 2018 Dec;42(12):3997-4004. doi: 10.1007/s00268-018-4737-0. PMID: 30039286.

Wu, H., Chen, Y., Liang, J. et al. Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis. Nature 438, 981–987 (2005). https://doi.org/10.1038/nature04225

Yamaguchi, S., Asanoma, K., Takao, T., Kato, K., & Wake, N. (2009). Homeobox gene HOPX is epigenetically silenced in human uterine endometrial cancer and suppresses estrogen-stimulated proliferation of cancer cells by inhibiting serum response factor. International Journal of Cancer, 124(11), 2577-2588. https://doi.org/10.1002/ijc.24217

Yusufu A, Shayimu P, Tuerdi R, Fang C, Wang F, Wang H. TFF3 and TFF1 expression levels are elevated in colorectal cancer and promote the malignant behavior of colon cancer by activating the EMT process. Int J Oncol. 2019;55:789–804.

Zhang M, Wang B, Chong QY, Pandey V, Guo Z, Chen RM, Wang L, Wang Y, Ma L, Kumar AP, Zhu T, Wu ZS, Yin Z, Basappa, Goh BC, Lobie PE. A novel small-molecule inhibitor of trefoil factor 3 (TFF3) potentiates MEK1/2 inhibition in lung adenocarcinoma. Oncogenesis. 2019 Nov 4;8(11):65. doi: 10.1038/s41389-019-0173-8. PMID: 31685806; PMCID: PMC6828705.

Zhou, Y., Shen, J., Xia, L. et al. Estrogen mediated expression of nucleophosmin 1 in human endometrial carcinoma clinical stages through estrogen receptor-α signaling. Cancer Cell Int 14, 540 (2014). https://doi.org/10.1186/s12935-014-0145-1

Zhou Y, Wang C, Mao L, Wang Y, Xia L, Zhao W, Shen J, and Chen J. Long noncoding RNA HOTAIR mediates the estrogen-induced metastasis of endometrial cancer cells via the miR-646/NPM1 axis. Am J Physiol Cell Physiol 314: C690–C701, 2018. doi:10.1152/ajpcell.00222.2017