Upstream eventIncreased, Ductal Hyperplasia
N/A, Breast Cancer
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Estrogen receptor activation leading to breast cancer||adjacent||High||High|
|Increased DNA damage leading to increased risk of breast cancer||adjacent||High||Not Specified|
|Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer||adjacent||High||Not Specified|
Life Stage Applicability
Key Event Relationship Description
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 Supporting this KER
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.
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.
Factors that increase proliferation or hyperplasia also increase tumors. Proliferative epithelial cells, nodules and hyperplasia appear in mammary gland of rats and mice after exposure to chemical carcinogens (Beuving, Bern et al. 1967; Beuving, Faulkin et al. 1967; Russo, Saby et al. 1977; Purnell 1980) and ionizing radiation (Faulkin, Shellabarger et al. 1967; Ullrich and Preston 1991; Imaoka, Nishimura et al. 2006; Nguyen, Oketch-Rabah et al. 2011; Snijders, Marchetti et al. 2012; Suman, Johnson et al. 2012; Tang, Fernandez-Garcia et al. 2014). A subpopulation of post-senescent epithelial cells also proliferate following IR in vitro (Mukhopadhyay, Costes et al. 2010).
Proliferation and hyperplasia precede or are detected at the same time as tumors (Beuving, Bern et al. 1967; Beuving, Faulkin et al. 1967; Faulkin, Shellabarger et al. 1967; Haslam and Bern 1977; Russo, Saby et al. 1977; Purnell 1980; Imaoka, Nishimura et al. 2005; Imaoka, Nishimura et al. 2006) and form tumors more effectively than non-proliferating tissue (Deome, Faulkin et al. 1959; Beuving 1968; Rivera, Hill et al. 1981). Adenocarcinomas appear to form from terminal end bud hyperplasia in rats (Haslam and Bern 1977; Russo, Saby et al. 1977; Purnell 1980), similar to the origin of many breast cancers for humans and for some mice after IR (Medina and Thompson 2000).
Interrupting or preventing proliferation or hyperplasia reduces the incidence (or growth) of tumors. Disruption of proliferation or hyperplasia formation disrupts tumor growth (Luo, Fan et al. 2009; Connelly, Barham et al. 2011; Tang, Fernandez-Garcia et al. 2014). Similarly, ACI rats exhibit no proliferation or hyperplasia following IR and are resistant to tumors following IR (Shellabarger, Stone et al. 1976; Kutanzi, Koturbash et al. 2010).
Uncertainties and Inconsistencies
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).
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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.
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.
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.
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. (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.
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.
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.
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.
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.
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.
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.