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Relationship: 1252


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

Increased, Ductal Hyperplasia leads to N/A, Breast Cancer

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

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
Estrogen receptor activation leading to breast cancer adjacent High High Molly M Morgan (send email) Open for adoption
Increased DNA damage leading to increased risk of breast cancer adjacent High Not Specified Jessica Helm (send email) Under development: Not open for comment. Do not cite Under Development
Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer adjacent High Not Specified Jessica Helm (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 Do not cite Under Development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 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

Life Stage Applicability

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

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

Proliferative lesions are believed to evolve over time and with successive cell divisions to take on the hallmarks of carcinogenesis, either directly or via other cell types recruited to the site such as fibroblasts and macrophages.

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 is High. It is generally accepted that proliferation contributes to cancer. Proliferation increases mutations, which can further promote proliferation and/or changes to the local microenvironment.

Empirical support is High. Carcinogenic agents increase proliferation and hyperplasia as well as tumors. Proliferation and hyperplasia appears prior to or at the same time as tumors, grow into carcinomas, and are more effective at forming mammary tumors than non-proliferating tissue. Disruption of proliferation is associated with decreased tumor growth, and tumor resistant rats do not show proliferation. However, the discrepancy between the non-linear proliferative and linear mammary tumor response to carcinogen dose coupled with evidence of independent occurrences of proliferation and tumorigenesis suggests that while proliferation and hyperplasia likely promote carcinogenesis, additional factors also contribute.

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
 Biological Plausibility is High. It is generally accepted that proliferation contributes to cancer. Proliferation increases mutations, which can further promote proliferation and/or changes to the local microenvironment. For example, cells that become insensitive to certain TGF-β signaling pathways would be resistant to contact or TGF-β inhibition (Polyak, Kato et al. 1994) or apoptosis (Chapman, Lourenco et al. 1999), and cells that release or promote the stromal release of MMPs remodel the stroma and promote tumorigenesis and invasiveness (Sternlicht, Lochter et al. 1999; Ha, Moon et al. 2001).
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

In the relatively small number of studies that examine the dose-dependence of proliferation and hyperplasia in models of carcinogenesis, proliferation does not appear to increase linearly with dose (Han, Chen et al. 2010; Mukhopadhyay, Costes et al. 2010; Nguyen, Oketch-Rabah et al. 2011; Tang, Fernandez-Garcia et al. 2014) while tumor formation and carcinogenesis does increase linearly with dose.

Some studies report carcinogenesis in the absence of hyperplasia (Middleton 1965; Sinha and Dao 1974) and others do not find increased tumorigenesis from transplanted hyperplasia (Haslam and Bern 1977; Sinha and Dao 1977). In Copenhagen rats resistant to tumors from MNU treatment, hyperplasia appear after MNU treatment but do not progress into carcinomas in situ, instead disappearing over time (Korkola and Archer 1999). Similarly, Fisher rats are less sensitive to tumor induction by DMBA, and hyperplasia from these rats do not go on to form tumors when transplanted (Beuving, Bern et al. 1967).

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
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


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

Beuving, L. J. (1968). "Mammary tumor formation within outgrowths of transplanted hyperplastic nodules from carcinogen-treated rats." Journal of the National Cancer Institute 40(6): 1287-1291.

Beuving, L. J., H. A. Bern, et al. (1967). "Occurrence and Transplantation of Carcinogen-Induced Hyperplastic Nodules in Fischer Rats2." JNCI: Journal of the National Cancer Institute 39(3): 431-447.

Beuving, L. J., J. L. J. Faulkin, et al. (1967). "Hyperplastic Lesions in the Mammary Glands of Sprague-Dawley Rats After 7,12-Dimethylbenz[a]anthracene Treatment2." JNCI: Journal of the National Cancer Institute 39(3): 423-429.

Chapman, R. S., P. C. Lourenco, et al. (1999). "Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3." Genes & development 13(19): 2604-2616.

Connelly, L., W. Barham, et al. (2011). "Inhibition of NF-kappa B activity in mammary epithelium increases tumor latency and decreases tumor burden." Oncogene 30(12): 1402-1412.

Deome, K. B., L. J. Faulkin, Jr., et al. (1959). "Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice." Cancer Res 19(5): 515-520.

Faulkin, J. L. J., C. J. Shellabarger, et al. (1967). "Hyperplastic Lesions of Sprague-Dawley Rat Mammary Glands After X Irradiation2." JNCI: Journal of the National Cancer Institute 39(3): 449-459.

Ha, H. Y., H. B. Moon, et al. (2001). "Overexpression of membrane-type matrix metalloproteinase-1 gene induces mammary gland abnormalities and adenocarcinoma in transgenic mice." Cancer research 61(3): 984-990.

Han, W., S. Chen, et al. (2010). "Nitric oxide mediated DNA double strand breaks induced in proliferating bystander cells after alpha-particle irradiation." Mutation research 684(1-2): 81-89.

Haslam, S. Z. and H. A. Bern (1977). "Histopathogenesis of 7,12-diemthylbenz(a)anthracene-induced rat mammary tumors." Proceedings of the National Academy of Sciences of the United States of America 74(9): 4020-4024.

Imaoka, T., M. Nishimura, et al. (2006). "Persistent cell proliferation of terminal end buds precedes radiation-induced rat mammary carcinogenesis." In Vivo 20(3): 353-358.

Imaoka, T., M. Nishimura, et al. (2005). "Cooperative induction of rat mammary cancer by radiation and 1-methyl-1-nitrosourea via the oncogenic pathways involving c-Myc activation and H-ras mutation." Int J Cancer 115(2): 187-193.

Korkola, J. E. and M. C. Archer (1999). "Resistance to mammary tumorigenesis in Copenhagen rats is associated with the loss of preneoplastic lesions." Carcinogenesis 20(2): 221-227.

Kutanzi, K. R., I. Koturbash, et al. (2010). "Imbalance between apoptosis and cell proliferation during early stages of mammary gland carcinogenesis in ACI rats." Mutation research 694(1-2): 1-6.

Luo, M., H. Fan, et al. (2009). "Mammary epithelial-specific ablation of the focal adhesion kinase suppresses mammary tumorigenesis by affecting mammary cancer stem/progenitor cells." Cancer research 69(2): 466-474.

Medina, D. and H. J. Thompson (2000). A Comparison of the Salient Features of Mouse, Rat, and Human Mammary Tumorigenesis. Methods in Mammary Gland Biology and Breast Cancer Research. M. M. Ip and B. B. Asch. Boston, MA, Springer US: 31-36.

Middleton, P. J. (1965). "The histogenesis of mammary tumours induced in the rat by chemical carcinogens." British journal of cancer 19(4): 830-839.

Mukhopadhyay, R., S. V. Costes, et al. (2010). "Promotion of variant human mammary epithelial cell outgrowth by ionizing radiation: an agent-based model supported by in vitro studies." Breast cancer research : BCR 12(1): R11.

Nguyen, D. H., H. A. Oketch-Rabah, et al. (2011). "Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type." Cancer Cell 19(5): 640-651.

Polyak, K., J. Y. Kato, et al. (1994). "p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest." Genes & development 8(1): 9-22.

Purnell, D. M. (1980). "The relationship of terminal duct hyperplasia to mammary carcinoma in 7,12-dimethylbenz(alpha)anthracene-treated LEW/Mai rats." The American journal of pathology 98(2): 311-324.

Rivera, E. M., S. D. Hill, et al. (1981). "Organ culture passage enhances the oncogenicity of carcinogen-induced hyperplastic mammary nodules." In vitro 17(2): 159-166.

Russo, J., J. Saby, et al. (1977). "Pathogenesis of Mammary Carcinomas Induced in Rats by 7, 12-Dimethylbenz[a]anthracene2." JNCI: Journal of the National Cancer Institute 59(2): 435-445.

Shellabarger, C. J., J. P. Stone, et al. (1976). "Synergism between neutron radiation and diethylstilbestrol in the production of mammary adenocarcinomas in the rat." Cancer research 36(3): 1019-1022.

Sinha, D. and T. L. Dao (1974). "A Direct Mechanism of Mammary Carcinogenesis Induced by 7,12-Dimethylbenz[a]anthracene2." JNCI: Journal of the National Cancer Institute 53(3): 841-846.

Sinha, D. and T. L. Dao (1977). "Hyperplastic alveolar nodules of the rat mammary gland: tumor-producing capability in vivo and in vitro." Cancer letters 2(3): 153-160.

Snijders, A. M., F. Marchetti, et al. (2012). "Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility." PLoS One 7(10): e45394.

Sternlicht, M. D., A. Lochter, et al. (1999). "The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis." Cell 98(2): 137-146.

Suman, S., M. D. Johnson, et al. (2012). "Exposure to ionizing radiation causes long-term increase in serum estradiol and activation of PI3K-Akt signaling pathway in mouse mammary gland." International journal of radiation oncology, biology, physics 84(2): 500-507.

Tang, J., I. Fernandez-Garcia, et al. (2014). "Irradiation of juvenile, but not adult, mammary gland increases stem cell self-renewal and estrogen receptor negative tumors." Stem Cells 32(3): 649-661.

Ullrich, R. L. and R. J. Preston (1991). "Radiation induced mammary cancer." Journal of radiation research 32 Suppl 2: 104-109.