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Event: 1982

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

metastatic breast cancer

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

Metastasis, Breast Cancer

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Organ

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
DNA damage and metastatic breast cancer	AdverseOutcome	Usha Adiga (send email)	Under development: Not open for comment. Do not cite	Under Development

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 KE.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 in relation to this KE. More help

Term	Scientific Term	Evidence	Link
human and other cells in culture	human and other cells in culture	High	NCBI
human	Homo sapiens	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Adult	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Mixed	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Processs: metastasis of cancer cells Object:metastasis Process:Increased

Biological state:

Dissemination of the cancer cells from one organ to another which is not directly connected to the primary site is called metastasis. It has a crucial role in the prognosis of cancer patients. In the initial stage of metastasis, cancer cells detach from the primary tumor and disseminate in the tissue. Subsequently cancer cells enter the vascular or lymphatic channels (23-25). The establishment of micro-metastasis mainly depends on the survival of the circulating tumor cells (CTCs) inside the lymphatic or blood channels. Extravasation of cancer cells through the vessel wall takes place resulting in the proliferation of cancer cells in the secondary site. Various signalling pathways are involved in each of the above mentioned process. Few theories have been proposed to explain the mechanism of metastasis. The “organ selection concept” theory suggests that the growth factors establish a successful metastasis in the metastatic site (26,27) whereas the “adhesion theory” proposes the tissue specific adhesion molecules are expressed on endothelial cells of recipient organs which will anchor the migrating cancer cells, providing the a pre-metastatic niche. The role of chemokine receptor has been explained in “chemo-attraction theory” while Paget reported the theory of “seed” for metastatic tumor cells and of “soil” for the secondary site. As per this concept the organ distribution is determined by the site and histopathological type of the primary tumor. The recent understanding suggested, pre-metastatic niche has been indicated to explain metastasis. It is interesting to note that prior to co-localization, the primary tumor induces the micro environment of secondary site by CTCs.

Subsequently, a metastatic niche is generated to support disseminated tumor cells (DTCs) and localize them to develop a metastasis. The most recent theory describes a bidirectional relationship between the primary and secondary sites. According to this theory, the surviving cancer cells in the metastatic tumor can return to the primary site to promote the primary tumor progression (28,29). Efficient and direct blood flow can explain the probability of metastasis to the specific organs like hepatic metastasis in patients with colon cancer which receive direct blood flow from the primary site .Vascular permeability is also the other factor which significantly promotes extravasation at the metastatic site. However at present, understanding of molecular mechanisms of metastasis remains incomplete.

Biological compartment

Organs,Cellular

Role in general biology

Epithelial- mesenchymal transition (EMT) and its reverse mesenchymal-epithelial transition (MET) are characteristics of cellular plasticity during embryogenesis and tumor metastasis (30). There has been decreased expression of E-cadherin and β-catenin and elevated expression levels of vimentin, fibronectin and N-cadherin in EMT (31). In cancers, EMT is a major process by which cancer cells lose their epithelial characteristics to acquire mesenchymal-like properties. Tumor cell migration is a pre-requisite for the metastatic process in which, EMT is the most critical step to initiate metastasis including metastasis to lymph nodes (32). During EMT, cancer cells lose their cell-to-cell junctions and cellular polarity via multiple signaling pathways which increase the motilities and invasive phenotype of them (33). Cleavage of E-cadherin mediated by the MMPs increases the tumor cell motility and invasion . Apart from this ,EMT has a key role in drug resistance. This is supported by the finding that high levels of vimentin was found in adriamycin and vinblastine resistant breast cancer cell lines (34). EMT promotes CSCs motility, cancer cell invasion, tumor metastasis and recurrence and drug resistance. Expression of stem cell like markers and formation of tumor spheres by CSCs are enhanced by EMT process. CSCs acquire mesenchymal features by undergoing EMT phenomenon. By acquiring mesenchymal features, CSCs become resistant to anti-cancer therapies; hence, they can survive and cause cancer recurrence. In addition to this ,CSCs invade to the adjacent stromal tissues, enter the vascular channels, and finally reach the distant organs. In the target organs, CSCs cause MET phenomenon which results in the acquisition of epithelial characteristics. MET phenomenon also increases the cell-to-cell attachment, cancer cells proliferation and differentiation to form metastatic lesions (35). Altogether , EMT induces CSC properties and metastatic activities. On the other hand, EMT and CSCs collaborate in invasion capacity hence targeting the EMT/CSC phenotype can be a therapeutic approach for the treatment of metastasis and tumor recurrence (36).

EMT programs are regulated by a network of signal- ling pathways that involve components such as growth factors (transforming growth factor-β [TGF-β], epider- mal growth factor [EGF]) and their associated signalling proteins (Wnt, Notch, Hedgehog, nuclear-factor kappa B [NF-κB], extracellular signal-regulated kinase [ERK], and phosphatidylinositol 3-kinase [PI3K]/Akt) in response to stresses involved in tumorigenesis, including hypoxia, oncogenic or metabolic stress, inflammation, and physical constraints [37-41].

These signals activate EMT-inducing transcription factors, including Snail/Slug, ZEB1/δEF1, ZEB2/SIP1, Twist1/ 2, and E12/E47 [42-44]. EMT-inducing transcription factors regulate the expression of proteins involved in cell polarity, cell-cell contact, cytoskeletal structural maintenance, and extracellular matrix (ECM) degradation, and they sup- press key epithelial genes. Loss of E-cadherin is considered a hallmark of EMT; these EMT-inducing transcription factors bind to E-box elements in the E-cadherin gene promoter to repress its transcription. Of particular note, Snail is an early marker of EMT that is involved in the initial cell-migratory phenotype, and it occasionally induces other factors .

During EMT, epithelial cells reorganize cytoskeleton and resolve cell–cell junctions, which are accompanied with switching off the expression of epithelial markers and turning on mesenchymal genes. Although changes in epithelial and mesenchymal markers during EMT can vary significantly in different biologic contexts, a network of transcription factors, including TWIST1/2, SNAIL1/2, ZEB1/2, and FOXC2, are consistently required to orchestrate the EMT program (45). The expression of these transcription factors is associated with poor prognosis and distant metastasis in various human cancers has been documented in various studies. (46). Besides its role in promoting tumor cell invasion, EMT is shown to confer tumor cells with resistance to apoptosis and anoikis (47), thus allowing cell survival in the blood stream after intravasation. EMT could also facilitate tumor cells' escape from the senescence program, especially through TWIST1 and ZEB1 (48,49). Furthermore, EMT has been shown to cancer cells with cancer stem cell (CSC)–like features, which further aid tumor dormancy and chemo resistance (50,51).Tumor samples or experimental tumor xenograft models have provided convincing evidence for the activation of EMT in various primary epithelial tumors in various studies. . Interestingly, more recent studies reveal a dynamic requirement of EMT in tumor metastasis: activation of EMT promotes local tumor invasion, intravasation, and extravasation of the systemic circulation, whereas reversion of EMT is essential to establish macrometatasis in distant organs (52,53).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

	Method/ measurement reference	Reliability	Strength of evidence	Assay fit for purpose	Repeatability/ reproducibility	Direct measure
Cell line,humans,Human cell line studies	qRT-PCR,,Luciferase reporter assay ,immunoblotting,immunoprecipitation,cell invasion assay,cell migration assay, bioluminesence imaging,wound healing assay,Wound scratch & Transwell assay, Microarray,Immunofluorescence, Immunohistochemistry,	+	Strong	Yes	Yes	Yes

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Increased metastasis of cancerous cells is known to be highly conserved throughout evolution and is present from humans to invertebrates.

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

The Adverse Outcome Pathway (AOP) holds substantial regulatory significance as a structured framework for understanding and predicting the biological sequence of events leading from DNA damage to a metastatic breast cancer. By elucidating the causal relationships between key events along the pathway, AOP offer a comprehensive understanding of toxicological mechanisms and provide a basis for informed decision-making in risk assessment and regulatory decision-making. AOPs facilitate the integration of diverse scientific data, enabling regulators to evaluate the potential impact of chemical exposures on human health and the environment. These pathways empower the development of targeted testing strategies, alternative methods, and safer chemical design, ultimately enhancing the efficiency and accuracy of risk assessment and regulatory policies.

References

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

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