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Event: 1971

Key Event Title

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

Increased, tumor growth

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
tumor growth
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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 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; 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
Process Object Action
Breast carcinoma BRCA1-A complex increased

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
AhR activation to metastatic breast cancer KeyEvent Evgeniia Kazymova (send email) Under Development: Contributions and Comments Welcome 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
Homo sapiens Homo sapiens High NCBI

Life Stages

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

Tumor growth refers to the increase in size of a cancer due to the uncontrolled proliferation of cells. The mechanisms have been detailed in Hanahan et al. hallmarks of cancer:

  • Initiation: Tumor growth often begins with the initiation of genetic alterations in normal cells. This can result from mutations caused by various factors such as exposure to carcinogens, genetic predisposition, or viral infections.
  • Uncontrolled Cell Proliferation: One of the hallmark features of tumor growth is uncontrolled cell division. Initiating mutations in key regulatory genes, such as oncogenes and tumor suppressor genes, disrupt normal cell cycle control, leading to continuous and unregulated cell proliferation. The PI3K/AKT/mTOR pathway regulates cell growth, proliferation, and survival. Mutations in genes like PTEN, a negative regulator of this pathway, can lead to its hyperactivation, promoting tumor growth (Janaku, Paplomatta). The MAPK is involved in cell proliferation, differentiation, and survival. Mutations in genes like BRAF and KRAS can activate this pathway, contributing to uncontrolled cell growth and tumor development (Steelman, Guo).
  • Angiogenesis: Tumors require a blood supply for sustained growth. Angiogenesis, the formation of new blood vessels, is induced by the tumor to ensure a nutrient and oxygen supply. Tumor cells release pro-angiogenic factors, promoting the development of a network of blood vessels within and around the tumor (Nishida).
  • Metabolic Adaptations: Tumor cells often exhibit altered metabolism, characterized by increased glycolysis even in the presence of oxygen (Warburg effect). This metabolic shift supports the high energy demands of rapidly dividing cells (Pham).
  • Tumor Microenvironment: Tumor growth involves interactions with the surrounding microenvironment, including stromal cells, immune cells, and the extracellular matrix. Tumor cells can influence their microenvironment to promote their survival and expansion. Fibroblasts transform into cancer associated fibroblasts to support tumor growth by producing growth factors and promoting angiogenesis (Asif).
  • Immune Evasion: Malignant tumors can develop mechanisms to evade the immune system. This may involve downregulation of antigens, inhibitory signals to immune cells, or the recruitment of immunosuppressive cells, allowing the tumor to escape immune detection and attack (Hiam).
  • Invasion and Metastasis: Malignant tumors can invade nearby tissues and, in advanced stages, metastasize to distant organs. Invasion involves the penetration of tumor cells into surrounding tissues, while metastasis is the spread of cancer cells to other parts of the body via the bloodstream or lymphatic system.
  • Tumor Dormancy: In some cases, tumor growth may enter a state of dormancy, where the proliferation of cancer cells is temporarily halted. Dormant tumors can later resume growth, posing challenges in terms of early detection and treatment (Endo).

Detailed here are key molecular mechanisms associated with breast tumor growth (Hanahan):

  • Genetic Mutations: Genetic alterations in key oncogenes (e.g., HER2, MYC, PIK3CA) promote cell proliferation whereas mutations in tumor suppressor genes (e.g., TP53, BRCA1, BRCA2) remove inhibitory controls on cell growth. (Knudson)
  • Hormone Receptor Signaling: ER-positive breast cancers (70% of cancers) respond to estrogen stimulation, promoting cell proliferation. Endocrine therapies targeting ER signaling are effective in treating these cancers (Elikatkin).
  • HER2/Neu overexpression : Amplification or overexpression of the human epidermal growth factor receptor 2 (HER2) promotes cell growth and survival (Slamon, Elikatkin).
  • PI3K/AKT/mTOR Pathway Activation: Mutations in the PIK3CA gene or activation of PI3K signaling pathway promotes cell survival and proliferation. Phosphoinositide 3-kinase (PI3K) activation leads to downstream signaling through AKT and mTOR, promoting cell growth and protein synthesis (Janku, Paplomata)
  • MAPK pathway: This pathway is involved in cell proliferation, differentiation, and survival. Mutations in this pathway can also contribute to breast cancer development (Steelman).
  • Cell Cycle Regulation: Dysregulation of cyclin-dependent kinase (CDK) and cyclin complexes controls the cell cycle progression. Inactivation of the p16 tumor suppressor and retinoblastoma protein (pRB) pathway contributes to uncontrolled cell cycle progression (Witkiewicz).
  • Apoptosis Evasion: Overexpression of anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL) inhibits programmed cell death. Mutations or inactivation of pro-apoptotic proteins (e.g., p53) hinders apoptotic responses.
  • Angiogenesis Stimulation: Vascular endothelial growth factor (VEGF) and its receptors stimulate angiogenesis, ensuring a blood supply for tumor growth. Hypoxia-inducible factor 1-alpha (HIF-1α) activates angiogenic responses in low-oxygen conditions.
  • Epithelial-Mesenchymal Transition (EMT): Downregulation of adhesion molecules (e.g., E-cadherin) leads to increased cell mobility. Acquisition of mesenchymal characteristics enhances the ability of tumor cells to invade surrounding tissues (Drasin).
  • Extracellular Matrix (ECM) Remodeling: Overexpression of MMPs facilitates ECM degradation, enabling tumor invasion.
  • Metastasis Formation: Tumor cells invade surrounding tissues and enter blood or lymphatic vessels. Ability of tumor cells to survive in the bloodstream. Tumor cells exit circulation, invade distant tissues, and establish secondary tumors.

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

Many different assays can be used to measure tumor growth directly:

  • Clinical measurement and palpation
  • Histopathology with fluorescence imaging, dyes or weight
  • Serum Biomarkers
  • Imagery using caliper measurement on Magnetic Resonance Imaging (MRI), Computed Tomography (CT), Positron Emission Tomography (PET), or ultrasound can provide detailed images for volume calculation.
  • Positron Emission Tomography (PET) Imaging : measurement of metabolic activity using radioactive tracers.
  • In vivo models: xenograft tumor models, orthotopic models, genetically engineered mouse models

Indirect assays can also be used:

  • Bioluminescence Imaging (BLI): Measurement of light emitted by luciferase-expressing tumor cells.
  • Flow Cytometry: Quantification of tumor cells based on DNA content.
  • Cell Proliferation Assays (MTT/MTS, BrdU)
  • Colony formation

Domain of Applicability

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

Human, mice


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

Asif PJ, Longobardi C, Hahne M, Medema JP. The Role of Cancer-Associated Fibroblasts in Cancer Invasion and Metastasis. Cancers (Basel). 2021 Sep 21;13(18):4720. doi: 10.3390/cancers13184720. PMID: 34572947; PMCID: PMC8472587.

Witkiewicz AK, Knudsen ES. Retinoblastoma tumor suppressor pathway in breast cancer: prognosis, precision medicine, and therapeutic interventions. Breast Cancer Res. 2014 May 7;16(3):207. doi: 10.1186/bcr3652. PMID: 25223380; PMCID: PMC4076637.

Eliyatkın N, Yalçın E, Zengel B, Aktaş S, Vardar E. Molecular Classification of Breast Carcinoma: From Traditional, Old-Fashioned Way to A New Age, and A New Way. J Breast Health. 2015 Apr 1;11(2):59-66. doi: 10.5152/tjbh.2015.1669. PMID: 28331693; PMCID: PMC5351488.

Phan LM, Yeung SC, Lee MH. Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biol Med. 2014 Mar;11(1):1-19. doi: 10.7497/j.issn.2095-3941.2014.01.001. PMID: 24738035; PMCID: PMC3969803.

Nishida N, Yano H, Nishida T, Kamura T, Kojiro M. Angiogenesis in cancer. Vasc Health Risk Manag. 2006;2(3):213-9. doi: 10.2147/vhrm.2006.2.3.213. PMID: 17326328; PMCID: PMC1993983.

Drasin, D.J., Robin, T.P. & Ford, H.L. Breast cancer epithelial-to-mesenchymal transition: examining the functional consequences of plasticity. Breast Cancer Res 13, 226 (2011).

Paplomata E, O'Regan R. The PI3K/AKT/mTOR pathway in breast cancer: targets, trials and biomarkers. Ther Adv Med Oncol. 2014 Jul;6(4):154-66. doi: 10.1177/1758834014530023. PMID: 25057302; PMCID: PMC4107712.

Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y and Hu LL: ERK/MAPK signalling pathway and tumorigenesis (Review). Exp Ther Med 19: 1997-2007, 2020

Hiam-Galvez, K.J., Allen, B.M. & Spitzer, M.H. Systemic immunity in cancer. Nat Rev Cancer 21, 345–359 (2021).

Endo H, Inoue M. Dormancy in cancer. Cancer Sci. 2019 Feb;110(2):474-480. doi: 10.1111/cas.13917. Epub 2019 Jan 11. PMID: 30575231; PMCID: PMC6361606.

Slamon, D. J., Godolphin, W., Jones, L. A., Holt, J., Wong, S. G., Keith, D. E., ... & McGuire, W. L. (1989). Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science (New York, N.Y.), 248(4960), 787-792.

Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57-70.

Knudson, A. G. (2000). Two-hit hypothesis for inherited breast cancer: an update. Carcinogenesis, 21(3), 439-448.

Janku, F., Yap, T. A., & Westin, J. (2018). Targeting the PI3K pathway in human cancer: rationale and emerging clinical landscapes. Journal of Clinical Oncology, 36(15), 1550-1562.

Steelman, L. S., Chappell, W. P., deCarvalho, T. B., Lowe, S., & Davies, M. (2004. Ras/Raf/MEK/