Aop: 439

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 the AhR leading to breast cancer

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
AhR activation to breast cancer

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
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Authors

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

Xavier Coumoul

Robert Barouki

Meriem Koual

Karine Audouze

Celine Tomkiewicz

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
Louise Benoit   (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
  • Louise Benoit
  • Mathieu Vinken

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under Development: Contributions and Comments Welcome
This AOP was last modified on November 14, 2022 03:03

Revision dates for related pages

Page Revision Date/Time
Activation, AhR March 22, 2018 14:00
Increase, Inflammation January 30, 2019 10:26
Apoptosis August 05, 2021 19:35
Increased, Motility September 16, 2017 10:17
Increased, Migration (Endothelial Cells) September 16, 2017 10:17
Increased, Invasion September 16, 2017 10:17
Increase, angiogenesis April 17, 2017 10:26
N/A, Breast Cancer May 08, 2019 14:14
Increased, tumor growth February 15, 2022 15:16
Activation, AhR leads to Increase, Inflammation February 15, 2022 15:22
Activation, AhR leads to Apoptosis February 15, 2022 15:23
Activation, AhR leads to Increased, Motility February 15, 2022 15:23
Activation, AhR leads to Increased, Migration (Endothelial Cells) February 15, 2022 15:23
Activation, AhR leads to Increased, Invasion February 15, 2022 15:24
Increase, Inflammation leads to Increased, Invasion February 15, 2022 15:24
Increase, Inflammation leads to Increase, angiogenesis February 15, 2022 15:25
Increased, Motility leads to Increased, Invasion December 03, 2016 16:38
Increased, Migration (Endothelial Cells) leads to Increase, angiogenesis February 15, 2022 15:26
Increased, Invasion leads to N/A, Breast Cancer February 15, 2022 15:26
Apoptosis leads to tumor growth February 15, 2022 15:26
Increase, angiogenesis leads to N/A, Breast Cancer February 15, 2022 15:27
tumor growth leads to N/A, Breast Cancer February 15, 2022 15:27
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) February 09, 2017 14:32

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

Breast cancer is the deadliest cancer in women with a poor prognosis in case of metastatic breast cancer. The role of the environments in the formation of metastasis has been suggested. We hypothesized that activation of the AhR (MIE), a xenobiotic receptor, could lead to breast cancer metastasis (AO), through different KEs, constituting a new AOP.

An artificial intelligence tool (AOP-helpfinder), which screens the available literature, was used to collect all existing scientific abstracts to build a novel AOP, using a list of key words. Four hundred and seven abstracts were found containing at least a word from our MIE list and either one word from our AO or KE list. A manual curation retained 113 pertinent articles, which were also screened using PubTator. From these analyses, an AOP was created linking the activation of the AhR to breast cancer related death through decreased apoptosis, inflammation, endothelial cell migration, and increased mortality. These KEs promote an increased tumor growth, angiogenesis and invasion which leads to breast cance metastasis.

The evidence of the proposed AOP was weighted using the tailored Bradford Hill criteria and the OECD guidelines (from the OECD user handbook, https://www.oecd.org/gov/Handbook.pdf). The confidence in our AOP and the biological plausibility was considered strong. Indeed, in vitro and in vivo findings on multiple types of breast cancers (with or without oesrtogen receptors, for instanace) supported our proposed AOP. An in vitro validation must be carried out, but our review proposes a strong relationship between AhR activation and breast metastasis with an innovative use of an artificial intelligence literature search.

This work was published in Envionnmental International: https://doi.org/10.1016/j.envint.2022.107323

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

Breast cancer is a frequent disease, responsible of 2 262 419 new cases and 684 996 deaths in 2020 in the world, making it the deadliest female cancer (Bray et al., 2018). In 70% of cases, the disease is localized, and the prognosis is favorable with a 5-year survival of 99%. However, once the disease spreads (lymph nodes, metastasis), survival is severely altered with a 5-year survival rate of 26% in case of metastasis (Henley et al., 2020). It is therefore of paramount importance to understand the mechanisms of metastasis in breast cancer.

Amongst risk factors clearly established, including obesity, genetic mutations and hormonal exposure, the importance of the role of the environment is currently emerging (Koual et al., 2020 Nov 17). In an epidemiologic study, we found a positive association between the concentrations of 2.3.7.8-TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxine) in the adipose tissue surrounding the tumors, and breast cancer metastasis in overweight and obese patients (Koual et al., 2019). Moreover, we have shown that, using both in vivo and in vitro models, TCDD exposure could promote an aggressive phenotype to breast cancer cells, thus favoring the formation of metastatic cells (Koual et al., 2021). TCDD is a potent ligand of the aryl hydrocarbon receptor (AhR), a transcriptional factor involved notably in the metabolism of xenobiotics (Larigot et al., 2022). Hence, the impact of the environment on breast cancer aggressiveness could be mediated by the activation of the AhR.

Interest is growing on the role of the AhR in breast cancer. First, the AhR is often overexpressed in different breast cancer cell lines (Zudaire et al., 2008Kim et al., 2000 Nov 16Li et al., 2014). Interestingly, the level of expression can be correlated to the stage or the molecular sub-type of the disease (Zudaire et al., 2008Zhao et al., 2013). Second, the AhR pathway has been associated with different pro-metastatic features in breast cancer, such as resistance to apoptosis, invasiveness, modified cell cycle, migration and proliferation (Zudaire et al., 2008Goode et al., 2013 Dec 15Kanno et al., 2006). Triple negative cell lines, breast cancer cell lines with the worse prognosis (not over-expressing Her2 receptor or hormonal receptors), over-expressing the AhR seem to develop stem-like characteristics, favoring epithelial-mesenchymal transition (EMT) and thus metastasis (Stanford et al., 2016). Thirdly, the AhR could be involved in the resistance of breast cancer to treatments (Goode et al., 2013 Dec 15Goode et al., 2014): after AhR knockout, Goode et al. found enhanced sensitivity of paclitaxel (a drug targeting cancer cells) in triple negative breast cancer, a cancer particularly difficult to treat (Goode et al., 2014). Breast cancer patients expressing estrogen receptors (ER-positive) in their cancer cells, can benefit from an efficient endocrine therapy, which greatly improves their survival. Activation of the AhR can lead to the loss of expression of the ER alpha and therefore to the loss of a potential therapeutic target (Safe et al., 2000 Jul).

The mechanisms linking the activation of the AhR to breast cancer aggressiveness are still unclear. Based on the AOP-wiki database (https://aopwiki.org/, last accessed March 2022), the central repository for AOPs, the AhR has already been proposed in several AOPs, but never in one characterized by the AO breast cancer metastasis. Likewise, an AOP linking an MIE to breast cancer aggressiveness has never been proposed. From our expertise and available knowledge, we hypothesize that the activation of the AhR could be a MIE leading to breast cancer related death (AO) through different KEs and KERs.

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

1. Data input, automatic identification, and extraction of the available knowledge

An artificial intelligence based method, named AOP-helpFinder (https://aop-helpfinder.u-paris-sciences.fr/index.php), was used to scope the available relevant literature (Carvaillo et al., 2019Zgheib et al., 2021Rugard et al., 2020 Jan 1Jornod et al., 2020Jornod et al., 2022). This tool screens the contents of abstracts from the PubMed database using lists of key words, including stressors, MIEs, KEs and AOs. It then automatically finds, and extracts links co-mentioned in abstracts between pairs of events (MIE/KE/AO) and ranks them using graph theory. In the proposed study, the key words included MIEs (AhR …), KEs (migration, hypoxia, colony…) and an AO (breast cancer, mammary tumor…). All biological events used for the screening were defined using AOP-wiki database and personal keywords. We first scanned the list of KE and KER proposed by AOP wiki and retained words and concepts which concerned cancer aggressivity. Personal keywords were added if necessary (ex: EMT). We reviewed the list of words as a team in order to be as extensive as possible. The key words used can be found in Supplementary Table S1.

The obtained results (i.e., abstracts co-mentioning KE and AO) were manually curated to refine them, and keep the most significant knowledge. First only the abstracts were read and if the article was kept, the full text was reviewed. A manual curation decision tree was created to only include articles that concerned: i) the AhR, ii) breast cancer, iii) cancer progression and not initiation and iv) reviews were excluded (details in results §1 AOP-helpFinder text mining tool).

The newly established version of the AOP-helpFinder tool was applied on the more than 30 million available abstracts from PubMed database, which allowed us to use the two proposed options: i) the refinement filter based on machine learning method (lemmatization process of text) combined with deletion of words of context in order to improve the accuracy of the outputs, and ii) the reduced search option which allow to screen only a part of the abstracts (Jornod et al., 2022). This allows to not screen the introductory part of an abstract which usually refer to a study hypothesis, with the aim to decrease false positives.

In order to cross-check the selected concepts, and to support the evidence in favor of the proposed AOP, all selected articles (after text mining and manual curation) were run through the PubTator Central tool (https://www.ncbi.nlm.nih.gov/research/pubtator/). PubTator is a web-based system that screens PubMed abstracts and PMC full-text articles for biomedical concepts (genes, diseases, mutations, species, cell lines) (Wei et al., 2013Wei et al., 2019 Jul 2). The PMIDs of the selected articles were used, and PubTator scanned their abstracts. The system overview is detailed by Wei et al. here (Wei et al., 2019 Jul 2). The retrieved chemical, disease, species, cell line and gene concepts were used to support the developed AOP.

2. AOP – Knowledge integration and weight of evidence assessment

The AOP was then developed using all the previously extracted data, using the OECD handbook (OECD, 2018). The graphical linear flow diagram was used to represent our proposed AOP.

The evidence supporting the AOP was organized and evaluated according to the tailored Bradford-Hill criteria, as described by OECD guidance (OECD, 2018Hill, 1965). Briefly, these criteria are a group of minimal conditions for providing adequate evidence of a causal relationship between 2 events.

First, the OECD guidelines were used to evaluate the weight of evidence (WoE) between each KE. The biological applicability domain of each KE was assessed for sex, life stage and taxa. Due to the heterogeneity of breast cancer, another category was added, namely whether the KE is present only in certain types of cancer (ER-positive, triple negative, Her2 overexpression). The types of assays used to measure the KE were also recorded. Then, the confidence in the essentiality of each KE was evaluated using the system proposed by the OECD (high, moderate, low) and detailed in the guidebook.

Second, the tailored Bradford-Hill criteria modified to fit the AOP evidence assessment were used as proposed previously to evaluate each KER (Vinken et al., 2013Becker et al., 2015): i) the concordance of dose–response relationships (ex: is there more migration with higher dosage AhR activators?), ii) the temporal concordance among the KER and AO (ex: is there cell migration before activation of the AhR?), iii) strength, consistency, and specificity of association (ex: use of specific AhR antagonists, silencing or knock out), iv) biological plausibility, coherence, and consistency of the experimental evidence (ex: number of studies finding the association, concordance amongst cell lines), and v) alternative mechanisms that logically present themselves and the extent to which they may distract from the postulated AOP (ex: use of different stressors).

Third, the OECD guidelines were used to evaluate the KERs: i) biological plausibility (mechanistic approach), ii) empirical support (dependent change and the experimental data present), iii) evidence and finally iv) quantitative evidence (closely linked to the tailored Bradford-Hill criteria). These were evaluated using the system proposed by the OECD (high, moderate, low) and detailed in the guidebook.

Finally, the AOP was overall assessed using the three primary considerations: the biological plausibility, the essentiality of each KE and the empirical support of KERs. Since the detail of the evaluation of the overall weight assessment of the AOP is not described in the OECD guidebook, this evaluation was subjective and decided by our team using all the different elements studied before.

3.Results

A total of 17,760 articles related to the MIE, AhR or aryl hydrocarbon receptor, were identified in the PubMed database (as of December 2021). This list of AhR-related abstracts was used to screen the ones concerning the putative AOP. All abstracts had to mention at least one event from the AO list (breast cancer or synonym) and one event from the KE list (KEs leading to metastasis: invasion, stemness…). The list of key words used for searching AOs and KEs can be found in Supplementary Table 1. After merging the identified abstract using their PubMed identifications (PMID), only 407 abstracts were kept from the AhR list with both a key event from our AO list and our KE list A total of 17,760 articles related to the MIE, AhR or aryl hydrocarbon receptor, were identified in the PubMed database (as of December 2021). This list of AhR-related abstracts was used to screen the ones concerning the putative AOP. All abstracts had to mention at least one event from the AO list (breast cancer or synonym) and one event from the KE list (KEs leading to metastasis: invasion, stemness…). The list of key words used for searching AOs and KEs can be found in Supplementary Table 1. After merging the identified abstract using their PubMed identifications (PMID), only 407 abstracts were kept from the AhR list with both a key event from our AO list and our KE list .

Four steps were used for the manual curation, that was performed by several experts. First, all the abstracts were screened to check if it indeed concerned the AhR. One hundred and thirty-four abstracts were excluded mainly because the retrieved “ahr” do not concern the aryl hydrocarbon receptor but the adjusted hazards ratio. Moreover, “ahr” sometimes referred to the last name of an author (Ex: Andre Ahr). Then, only abstracts concerning breast cancer were included. Eighteen abstracts were excluded because they did not directly concern breast cancer. One hundred and nine articles were not selected because they concerned breast cancer initiation and not aggressiveness / metastasis. Finally, 33 articles were reviews and not original works. In total, 113 articles were considered to develop our AOP.

The 113 articles were then classified by category in the metastatic process (migration, invasion…). Each category represented a hallmark of cancer and was associated with the corresponding key words that were used to explore Pubmed using AOP-helpFinder.

The 113 articles were also run through the PubTator Central tool to screen for biomedical concepts. The most frequently found disease was breast cancer, followed by toxicity and concepts concerning metastasis and aggressivity. TCDD (or dioxin, or 2,3,7,8-tetrachlorodibenzo-p-dioxin) was by far the most used chemical followed by estrogen, indole-3-carbinol, alpha-naphthoflavone, polycyclic aromatic hydrocarbons and hexachlorobenzene, mainly ligands of the AhR. Most identified studies concerned humans or mice, except one on zebrafish. The ER-positive cell line MCF-7 was the most frequently studied, followed by the aggressive MDA-MB-231 (triple negative) cell line. Without surprise, the AhR was the “gene concept” the most assessed followed by the estrogen receptor, CYP1A1 and CYP1B1. All results are displayed in Supplementary data S2. These results guided the concepts used in our AOP and the biological applicability domain.

After a careful read of the selected articles by all experts and based on their expertise, an adverse outcome network (AON) using 6 different linear AOPs

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

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 18 Activation, AhR Activation, AhR
KE 149 Increase, Inflammation Increase, Inflammation
KE 1262 Apoptosis Apoptosis
KE 1241 Increased, Motility Increased, Motility
KE 1190 Increased, Migration (Endothelial Cells) Increased, Migration (Endothelial Cells)
KE 1196 Increased, Invasion Increased, Invasion
KE 1376 Increase, angiogenesis Increase, angiogenesis
KE 1971 Increased, tumor growth tumor growth
AO 1193 N/A, Breast Cancer N/A, Breast Cancer

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

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

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Adult High

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
humans Homo sapiens High NCBI
mice Mus sp. High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Female High
Male Low

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

The biological plausibility of KERs is defined by the OECD as the « understanding of the fundamental biological processes involved and whether they are consistent with the causal relationship being proposed in the AOP ». The biological plausibility is strong due to the presence of overwhelming evidence present in different studies. A minor setback would be the difficulty to dismiss alternative mechanisms caused by the ligands used for AhR activation. This is detailed in the discussion.

The essentiality of KEs refers to « experimental data for whether or not downstream KEs or the AO are prevented or modified if an upstream event is blocked ». The essentiality of KEs is strong: most works use suppression or inhibition of the AhR (knock out, antagonists and/or silencing) with results coherent with our findings.

Finally, the empirical support of KERs, is often « based on toxicological data derived by one or more reference chemicals where dose–response and temporal concordance for the KE pair can be assessed ». The overall assessment of the empirical support of our KERs is also strong. There is evidence in human cell lines and mice showing a dose–response and temporal concordance for severity of our KE and the presence of metastasis.

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

The biological applicability domain of the putative AOP concerned mainly females of menstrual of post-menopausal age. Indeed, existing cell lines were derived from women of menstrual of post-menopausal age and in vivo, studies were performed on mice of reproductive age. Only one study used the zebra fish larvae (Narasimhan et al., 2018 May 7). However, it could be extrapolated to men. Indeed, breast cancers in men present similar tumor characteristics and no work has found diverging functions of the AhR between men and women. Moreover, no difference in AhR expression has been characterized between men and women. Furthermore, our AOP concerns ER-positive and triple negative cells lines.

Studies were carried out in humans, mice, and zebrafish (xenotransplant studies, no mammary gland) (i.e. PubTator results) and it can be hypothesized that this AOP is conserved across mammals. Indeed, the AhR is a very conserved and ancient protein (Hahn, 2002 Sep 20). However, since the sensitivity to adverse events are variable among taxa, we can only postulate this AOP in human and mice (Korkalainen et al., 2001 Aug 3Cohen-Barnhouse et al., 2011 JanDoering et al., 2013 Mar).

The AhR is a fascinating yet complex receptor since its activation is ligand and cell dependent. To avoid more bias, we decided to limit our AOP to breast cancer. First, this cancer is the most frequent female malignancy, which makes it a major public health concern. Second, this illness is hormonal-dependent and therefore the impact of the environment, through the AhR, can be strongly suggested. However, we have reasons to believe this AOP could be extrapolated to other cancers which share common regulatory pathways (Larigot et al., 2022). The AhR is overexpressed not only in breast cancer but also in lung, liver, stomach, head & neck, cervix, and ovarian cancer (Stanford et al., 2016DiNatale et al., 2010 Aug 6Liu et al., 2013 AugStanford et al., 2016 Aug). Moreover, in these cancers, the level of expression is correlated to the stage of the disease (Zudaire et al., 2008Koliopanos et al., 2002 Sep 5Chang et al., 2007 Jan 1). Additionally, Moenniks et al. found that mice with constitutively active AhR had more liver tumors than wild type mice (55% versus 6%) (Moennikes et al., 2004 Jul 15). In vitro evidence suggests that the AhR activation could promote a more aggressive phenotype to renal, lung, head and neck, and urothelial cancer through an increase in invasion, migration, and resistance to apoptosis which constitute representative key events of our AOP (Zudaire et al., 2008Stanford et al., 2016 AugIshida et al., 2015 Jul 15Ishida et al., 2010 FebDiry et al., 2006 Sep 7John et al., 2014 Oct). Besides, an AOP associating AhR activation and lung cancer initiation is currently under development (AOP, 2021) (https://aopwiki.org/aops/417, accessed May 2022).

Likewise, our AOP covers only breast cancer progression and not initiation. The mechanisms of breast cancer initiation are different from the metastatic pathway, but the AhR could also be involved in breast cancer initiation. In vitro, it was noted that human mammary benign cells with a high level of AhR had an increase in cell proliferation, and migration, and potentially display EMT-like features (Brooks and Eltom, 2011 Jun). In vivo, mice fed with 7,12-dimethylbenz[a]anthracene (DMBA, an AhR activator and a potent mutagen) had an increased risk of mammary tumors, with higher AhR expression (Currier et al., 2005). Strangely in regard of the deadly outcomes associated with aggressive breast tumors, the number of studies focusing on this specific aspect of mammary carcinogenesis is limited and therefore, epidemiological data on the effects of the exposome in breast cancer aggressiveness is scarce. Indeed, occupational exposure is difficult to quantify, and patients are usually exposed to a mixture of pollutants and not a single pollutant in a chronic way. A memory bias cannot be excluded since the half-life of TCDD, for instance, is 7–11 years (Pirkle et al., 1989). Industrial accidents, such as the Seveso incident, studied the increase in breast cancer incidence but did not record breast cancer aggressiveness since it is more complex to quantify. At an early stage, breast cancer has a favorable prognosis whereas the therapeutic challenge lies in the treatment of breast cancer metastases. Therefore, even though epidemiologic and cell evidence suggests that exposure to pollutants and Ahr activation could promote breast cancer initiation, we chose to study breast cancer progression, the most complex situation (Pesatori et al., 2009 SepWarner et al., 2002 Jul).

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
KEY EVENT LEVEL OF ESSENTIALITY EVIDENCE    
KE 1262 and KE 1971 : decreased apoptosis and tumor growth Strong

A decrease in apoptosis is an essentiel element in promoting tumor growth. Indeed, in case of a decrease in cell death, the tumor will continue to grow. However, cell proliferation is also an essentiel element in promoting tumor growth. However, due to the presence of diverging evidence on the activation of the AhR and cell proliferation, we chose not to include these in our AOP. Indeed, on one hand, activation of the AhR through ligands such as NK150460, ANI-7, emodine or derivates of revesterol decrease cell proliferation in ER-positive and ER-negative breast cancer cell lines. TCDD has been found to promote cell cycle arrest through phosphorylation of the retinoblastoma protein which binds to E2F. In ER-positive cell lines, beta-naphthoflavone mediated cell cycle arrest through an upregulation of P21. On the other hand, AhR activation could promote cell proliferation. Pearce et al. found that MCDF (6-methyl-1,3,8-trichlorodibenzofuran), an AhR agonist could stimulate cell proliferation with a dose-response concordance. Likewise, I3C, HCB, CPF and licorice could also promote cell proliferation. However, it seems that this cell proliferation is ER-dependent. Indeed, these ligands induced cell proliferation only in ER-positive cells lines with an effect dependent on the level of estrogen present in the medium. Whether this increase in ER-dependent cell proliferation can be independent of the AhR remains unclear. This increase in proliferation could also be mediated by the association of the RelA subunit of NF-kappaB with the AhR resulting in the activation of c-myc gene transcription in breast cancer cells. This would explain why Rodriguez et al. found that proliferation was modulated by the CYP1A1, independently of an exogenous ligand activation of the AhR. These complex effects, highly dependent on the context (cell types, medium content, type of ligand…) were therefore not included in our AOP despite the strong evidence.

An increase in tumor size is associated with breast cancer metastasis and is essential to the progression of the illness  (Hanahan and Weinberg, 2011 Mar 4).

   

KE 1241 and KE 1196: Increased cell motility and increased invasion

  The relation between cell migration and organ invasion is essntial and is already used in different AOPs (KER-1306, https://aopwiki.org/relationships/1306). Organ invasion can be promonted by cell migration, motility and inflammation.     

KE 149 and KE 1196:  Increased inflammation and organ invasion 

       
KE 149 and KE 1213 : Increased inflammation and angiogenesis        
KE 1190 and KE 1213:  Increased endothelial migration and angiogenesis        
         

Evidence Assessment

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

KER 1 and KER 2: Activation of the AhR leads to decreased apoptosis which promotes tumor growth

Several studies have found that the activation of the AhR by stressors such as TCDD, can promote a decrease in apoptosis (KER1), which is a deleterious event with regards to cancer (Al-Dhfyan et al., 2017 Jan 19Bekki et al., 2015). Additionally, an increase in cell death was found when blocking the AhR pathway using AhR silencing (RNA interference or knock-out), knockout cell lines or antagonists (CH223191 or alpha-naphthoflavone) (Goode et al., 2013 Dec 15Al-Dhfyan et al., 2017 Jan 19Bekki et al., 2015Regan Anderson et al., 2018). The most frequently used assay to evaluate apoptosis was cytometry with the use of Annexin V: this was performed with ER-positive cells lines (MCF-7, T-47D), triple negative cell lines (MDA-MB-231, HS 578), cells over-expressing the Her2 (SK-BR-3) and cells lines derived from cancer samples from patients (Goode et al., 2013 Dec 15Al-Dhfyan et al., 2017 Jan 19Bekki et al., 2015Regan Anderson et al., 2018Fujisawa et al., 2011).

For KER 2, in vivo, Goode et al. showed that the knockout of the AhR in mice reduced tumor growth through an increase of cell apoptosis (Goode et al., 2013 Dec 15).

The concordance of the evidence was classified as “moderate” since the aim of most studies was to evaluate the capacity to survive in an apoptosis-promoting environment (i.e., chemotherapeutic drugs). Indeed, they assessed the resistance to chemotherapy agents such as doxorubicin and paclitaxel and found that the concomitant inactivation of the AhR pathway could decrease the resistance to these chemotherapy agents through an increase in cell death when compared to cells with a functional (or expressed at sufficient levels) AhR (Goode et al., 2013 Dec 15Al-Dhfyan et al., 2017 Jan 19Bekki et al., 2015Regan Anderson et al., 2018Fujisawa et al., 2011). Since the environment was modified by the presence of chemotherapy, the hypothesis of an alternative pathway cannot be completely discarded. It must be noticed that the exact biological mechanisms linking the activation of the AhR to the decrease in apoptosis remains unclear. Indeed, Anderson et al. suggested that the AhR interacts with the glucocorticoid receptor (GR) and the hypoxia inducible factor-2α (HIF-2α) (Regan Anderson et al., 2018). The presence of the GR is associated with a poor prognosis, notably in triple negative breast cancer (Pan et al., 2011Moran et al., 2000 Feb 15). Indeed, this receptor is involved in survival and resistance to chemotherapy through up-regulation of c-myc, Bcl2 and Kruppel-like factor 5 (Pan et al., 2011Wu et al., 2004Li et al., 2017). Both GR and HIF 2α could be up regulated by the AhR. They then activate Brk (also known as PTK6), a ligand of EGFR (epidermal growth factor receptor), involved in the inhibition of apoptosis (Regan Anderson et al., 2018Li et al., 2012). Another possible mechanism suggested by Bekki et al. is that the decrease in apoptosis was caused by the induction of cyclooxygenase 2 (COX-2) and the NF-κB subunit RelB (Bekki et al., 2015). They both prevent apoptosis through induction of Bcl2, an anti-apoptotic factor (Tsujii and DuBois, 1995Vogel et al., 2007Thomas et al., 2020Baud and Jacque, 2008 DecDemicco et al., 2005 NovWang et al., 2007 AprLiu et al., 2001 May 25).

The relationship between decreased apoptosis and increase in tumor growth (KER 2) is not detailed here due to extensive evidence in the scientific literature (Hanahan and Weinberg, 2011 Mar 4).

KER 4: Activation of the AhR leads to an increased cell motility

The activation of the AhR can modulate cell motility in different types of breast cancers such as: ER-positive cells lines (MCF-7, T-47D, ZR-75–1), triple negative (MDA-MB-231, MDA-MB-435, HS-578-T, SUM149), and cells overexpressing the Her2 (SK-BR-3) (Goode et al., 2013 Dec 15Regan Anderson et al., 2018Parks et al., 2014 NovPontillo et al., 2011 AprQin et al., 2011 Oct 20Nguyen et al., 2016 Nov 15Novikov et al., 2016 NovMiret et al., 2016 JulShan et al., 2020 NovDwyer et al., 2021 FebNarasimhan et al., 2018 May 7Hsieh et al., 2012 Feb). Activation of the AhR with TCDD, butyl-benzyl phthalate, di-n-butyl phthalate, hexachlorobenzene, and benzo[a]pyrene can promote cell migration in different assays (Parks et al., 2014 NovPontillo et al., 2011 AprQin et al., 2011 Oct 20Novikov et al., 2016 NovMiret et al., 2016 JulShan et al., 2020 NovNarasimhan et al., 2018 May 7Hsieh et al., 2012 Feb). On the other hand, the use of AhR antagonists, AhR silencing or AhR knockout reversed this effect (Goode et al., 2013 Dec 15Regan Anderson et al., 2018Parks et al., 2014 NovPontillo et al., 2011 AprQin et al., 2011 Oct 20Novikov et al., 2016 NovShan et al., 2020 NovNarasimhan et al., 2018 May 7Hsieh et al., 2012 Feb). The most frequently used assays for evaluating cell migration were the scratch wound assay and the transwell chamber assay. Only three works evaluated the dose–response concordance of AhR activation with stressors and cell migration (Pontillo et al., 2011 AprMiret et al., 2016 JulShan et al., 2020 Nov). The evidence was therefore classified as “moderate”.

 KER 4 and 5 (existing KER 1306): Activation of the AhR leads to an increased cell motility which promotes organ invasion

The relation between cell migration and organ invasion has already been shown (KER-1306, https://aopwiki.org/relationships/1306). Since the 2 are closely linked, most articles studied both cell migration (chemo-tactic) and the capacity to invade the extra-cellular matrix. Cell invasion is indeed defined as the capacity of a cell to migrate and degrade/invade the extracellular matrix. In vitro, this process was evaluated mostly using transwell chamber with Matrigel® and the presence of matrix metalloproteinases (MMP). This effect was found in ER-positive cells, triple negative cell lines and cells overexpressing the Her2.

Due to the extensive robust and concordant literature of the link between activation of the AhR-increased cell motility-increased invasion-breast cancer progression, the confidence in these key events was rated as high. However, due to the use of ligands to activate the AhR, it cannot be completely ruled out that alternative pathways (independent of the AhR) can also contribute to these features. For instance, 2 main pathways seem to explain this increase in migration and invasion: the c-Src/HER1/STAT5b, and ERK1/2 pathways. Yet, these pathways seem only to explain the relation between the AhR activation and cell migration / invasion, when the ligand used is hexachlorobenzene, an organochlorinated pesticide (Pontillo et al., 2011 AprMiret et al., 2016 JulPontillo et al., 2013 May 1). Even though alternative mechanisms may present themselves, all studies blocked the AhR pathway and found a decrease in cell migration/invasion. The evidence for alternative mechanisms was therefore classified as “moderate” and the biological plausibility of KER was also classified as “moderate”.

 KER 7: Activation of the AhR leads to an increased invasion

The activation of the AhR through the use of different ligands (benzophenone, butyl benzyl phthalate, di-n-butyl phthalate, hexachlorobenzene, chlorpyrifos, TCDD) or the blockage of the AhR (silencing, KO or antagonism) increased or decreased cell invasion, respectively (Parks et al., 2014 NovQin et al., 2011 Oct 20Nguyen et al., 2016 Nov 15Miret et al., 2016 JulShan et al., 2020 NovNarasimhan et al., 2018 May 7Hsieh et al., 2012 FebPontillo et al., 2013 May 1Miller et al., 2005Belguise et al., 2007 Dec 15Yamashita et al., 2018 May 1Miret et al., 2020 May). The dose–response concordance for cell invasion was demonstrated using increasing doses of hexachlorobenzene, benzo[a]pyrene, chlorpyrifos and TCDD (Miret et al., 2016 JulShan et al., 2020 NovPontillo et al., 2013 May 1Miller et al., 2005Miret et al., 2020 May). To further explore cell invasion, Nguyen et al. created a model of a lymphatic barrier using a three-dimensional lymph endothelial cell as a monolayer co-cultured with spheroids of MDA-MB231 cells (Nguyen et al., 2016 Nov 15). They found that silencing or antagonizing the AhR (DIM) or activating the AhR (FICZ) respectively decreased or increased invasion of the lymphatic barrier.

On an organ level, in vivo, an increase in metastasis has been found in mice and zebrafish after the activation of the AhR with different ligands (butyl benzyl phthalate, di-n-butyl phthalate, hexachlorobenzene, TCDD) (Goode et al., 2014Shan et al., 2020 NovNarasimhan et al., 2018 May 7Hsieh et al., 2012 FebPontillo et al., 2013 May 1). In the zebrafish model, Narasimham et al. treated the animals either with triple negative MDA-MB-231 cells only (untreated) or with MDA-MB-231 cells treated with an AhR inhibitor (CB7993113 or CH22319) (Narasimhan et al., 2018 May 7). Untreated fish had significantly more metastasis (OR = 9, IC95%=3–35). Similar results were found using mice models (Goode et al., 2014Shan et al., 2020 NovNarasimhan et al., 2018 May 7Hsieh et al., 2012 FebPontillo et al., 2013 May 1).

KER 8: Activation of the AhR leads to an increased inflammation (existing in AOP 21)

In triple negative breast cell lines (MDA-MB436, MDA-MB-231) and ER-positive cell lines, it has been shown that the activation of the AhR can lead to an increase in inflammation. (Bekki et al., 2015Miller et al., 2005Yamashita et al., 2018 May 1Degner et al., 2009 JanVogel et al., 2011 Aug 1Kolasa et al., 2013 Apr 25Vacher et al., 2018Malik et al., 2019 Oct). The stressors mainly used to activate the AhR were TCDD followed by benzo[a]pyrene and 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhiP). After AhR inhibition (KO or antagonists), a decrease in inflammation biomarkers was found (Miller et al., 2005Yamashita et al., 2018 May 1Degner et al., 2009 JanVogel et al., 2011 Aug 1Kolasa et al., 2013 Apr 25). Assays evaluating cell inflammation were quantitative dosages of IL-6, IL-8 and Cox2 activity/expression. Cox-2 and IL-8 were amongst the top “gene concepts” retrieved by the PubTator Central tool, likewise, “inflammation” was frequently found as a disease concept. The most consensual pathway linking the AhR activation to cell inflammation was the NF-kB pathway (Vogel et al., 2011 Aug 1Kolasa et al., 2013 Apr 25). Only half of the studies found a dose–response relationship (Miller et al., 2005Kolasa et al., 2013 Apr 25Malik et al., 2019 Oct). No studies were carried out in vivo for breast cancer and therefore the concordance and evidence were classified as “moderate”.

AOP 21 also found the association between AhR activation and inflammation via COX 2 (Aryl hydrocarbon receptor activation leading to early life stage mortality, via increased COX-2) with a weight of evidence classified as “high”. Indeed, the AhR/ARNT heterodimer links to the dioxin responsive elements which in turn up-regulates COX-2 (66,67].

 KER 9: Inflammation promotes organ invasion

In the specific setting of AhR activation, only 2 studies showed the continuum between AhR activation – increased inflammation – increased invasion (Miller et al., 2005Yamashita et al., 2018 May 1). However, in general, there is extensive knowledge on the relationship between cell inflammation and organ invasion. First, COX-2 is expressed at higher levels in triple negative invasive breast cancers than in less aggressive ER-positive cancers (Gilhooly and Rose, 1999 AugLiu and Rose, 1996 Nov 15). COX-2 catalyzes the conversion of arachidonic acid into prostaglandin H2, a pro-inflammatory factor, and is therefore considered as a prognosis factor in breast cancer (Ristimäki et al., 2002 Feb 1Parrett et al., 1997 Mar). Transfection with COX-2 triple negative MDA-MB-435 cells increased cell migration 2-fold compared to control cells in a transwell-Matrigel® assay. Antagonism of COX-2 through an inhibitor (NS-398) reversed this action in a dose-dependent way (Singh et al., 2005 May). Second, in vivo, the use of anti-inflammatory treatments such as celecoxib (COX-2 inhibitor) can reduce tumor growth and spread (Harris et al., 2000 Apr 15). Finally, epidemiologic evidence suggests that inflammatory breast cancers have the worse prognosis. Indeed, the median overall survival of patients with inflammatory breast cancer compared with those with non-inflammatory breast cancer tumors is 4.75 years versus 13.40 years for stage III disease and 2.27 years versus 3.40 years for stage IV disease (Schlichting et al., 2012 AugFouad et al., 2017 Apr).

The mechanism of action of COX-2 are consensual. COX-2 promotes cell invasion through upregulation of MMPs (notably 2 and 9) (Takahashi et al., 1999 Oct 22Sivula et al., 2005 FebLarkins et al., 2006 Jul). Moreover, COX-2 could also activate the urokinase plasminogen activator (uPA) which degrades the basal membrane of epithelia (Singh et al., 2005 MayTakahashi et al., 1999 Oct 22Larkins et al., 2006 JulGuyton et al., 2000 Mar).

The relationship between inflammation and invasion is well document therefore the evidence was classified as “strong”.

 KER 10: Inflammation promotes angiogenesis

Likewise, two studies evaluated the specific continuum AhR activation – increased inflammation – increased angiogenesis (Pontillo et al., 2015 Nov 19Zárate et al., 2020 Aug). As previously mentioned, the AhR activation increases inflammation, notably through an increase in COX 2 (Bekki et al., 2015Miller et al., 2005Degner et al., 2009 JanPontillo et al., 2015 Nov 19Zárate et al., 2020 Aug).

COX-2 can promote angiogenesis through an increase in VEGF (Vascular endothelial growth factor) (Harris et al., 2014 Oct 10Kirkpatrick et al., 2002). In a pathologic study characterizing 46 breast cancer specimen using immunochemistry, it was found that the density of microvessels was significantly higher in patients with COX-2 expression than in those without expression (p = 0.03) (Costa et al., 2002 Jun). The relationship between COX-2 and angiogenesis has also been shown in gastric and colorectal cancer (Tsujii et al., 1998 May 29Uefuji et al., 2000 Jan). Indeed, colon carcinoma cells overexpressing COX-2 produce proangiogenic factors (VEGF, bFGF, TBF-β, PDGF, and endothelin-1), and stimulate endothelial migration and the formation of tube vessels. These effects were reversed by an inhibitor (NS-398). In vivo, Diclofenac, a COX-2 inhibitor, decreased angiogenesis in mice presenting a colorectal cancer (Seed et al., 1997 May 1). Likewise, in a murine model of breast cancer, celecoxib (a selective COX-2 inhibitor) reduced metastasis and tumor burden through a decrease of micro vessel density and VEGF (Yoshinaka et al., 2006 DecZhang et al., 2004 Sep). In clinical studies, patients with inflammatory breast cancers have increased levels of genes involved in angiogenesis such as VEGF (Van der Auwera et al., 2004 Dec 1). Patients with an inflammatory breast cancer benefit the most from anti-angiogenic treatment bevacizumab (Pierga et al., 2012 Apr).

The evidence was classified as “moderate” due to the lack of dose response studies.

 KER 11 and 12 (existing KER 1266 and 1267): Activation of the AhR leads to an increased endothelial migration which promotes angiogenesis

The activation of the AhR can lead to an increased endothelial cell migration. This was found when HMEC-1 or EA.hy926 cells were co-cultured with ER-positive MCF-7 cells and triple negative MDA-MB-231 cells (Pontillo et al., 2015 Nov 19Zárate et al., 2020 Aug). The assay mainly used was the Matrigel® / tube formation assay. Only one study found an increase in endothelial cell proliferation and not migration, therefore it was not kept as a KE (Pontillo et al., 2015 Nov 19). The main pathway explaining this relationship was again related to the activation of COX2 and subsequently to the increase in VEGF. The association between the activation of the AhR and endothelial cell migration was classified as “weak” since only 2 studies explored this feature, and both used hexachlorobenzene as a stressor. However, these works were robust with strong evidence, and both found a reversed association after AhR blockage. No contradicting results were found in the scientific literature.

As opposed to our work, another AOP displayed a link between AhR activation and angiogenesis (AOP 150) and found that activation of the receptor could decrease VEGF production with moderate evidence and quantitative understanding. It must be noted that these AOPs applied only to chicken, zebrafish, and certain rodents whereas our AOP concerns humans. As detailed further, the AhR presents a variability between species which must be considered.

For KER 12, Pontillo et al. treated mice with increasing doses of hexachlorobenzene and then calculated the vessel density in mammary fat pads (Pontillo et al., 2015 Nov 19). They found that mice treated with hexachlorobenzene had a higher vessel density with a dose–response concordance. Treatment by AhR antagonists completely reversed this association (Pontillo et al., 2015 Nov 19Zárate et al., 2020 Aug). The relationship between endothelial migration and angiogenesis was not detailed here since there is existing extensive knowledge (Lamalice et al., 2007 Mar 30Norton and Popel, 2016 Nov 14Ausprunk and Folkman, 1977 Jul 1). The KER 12 was considered as “strong”.

 KER 3, 6 and 13: Increased tumor growth, increased invasion, and increased angiogenesis lead to breast cancer metastasis

Due to extensive data in the scientific literature and the empirical evidence in favor of these KERs, these KERs were not detailed here.

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

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