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Increase, Mutations leads to Increase, Cell Proliferation (Epithelial Cells)
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer||adjacent||Moderate||Not Specified||Evgeniia Kazymova (send email)||Under development: Not open for comment. Do not cite||Under Development|
|Increased DNA damage leading to increased risk of breast cancer||adjacent||Moderate||Not Specified||Allie Always (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
Key Event Relationship Description
Mutations altering gene expression or protein activity can enable cells to escape growth inhibition by increasing resistance to apoptosis, or other inhibitory signals, or by escape of cell cycle checkpoints. Alternatively, mutations can stimulate growth by activating proliferative pathways such as EGFR.
Evidence Collection Strategy
Evidence Supporting this KER
Biological plausibility is High. Multiple mechanisms limit the proliferation of cells in healthy biological systems. Mutations in many of the genes controlling these mechanisms promote proliferation.
Empirical support is Moderate. Mutations that promote proliferation are frequently found in cancers, and both mutation and proliferation occur in response to tumorigenic stressors like ionizing radiation. Mutations appear over the same time frame or prior to the appearance of proliferation. Multiple uncertainties and conflicting evidence weaken this key event relationship. The two key events differ in their dose response- mutation but not proliferation increases with ionizing radiation dose. Furthermore, a single mutation is not necessarily sufficient to increase proliferation- proliferation typically requires multiple mutations or a change in the surrounding environment. In mammary tissue, stromal state – which is modified by hormones - strongly influences the proliferative nature of epithelial cells, and mutated epithelial cells alone appear to be insufficient for tumor growth.
High. Multiple mechanisms limit the proliferation of cells in healthy biological systems. Mutations in many of the genes controlling these mechanisms promote proliferation. Biological mechanisms such as contact inhibition, apoptosis, cell cycle checkpoints, and growth factor availability act to restrain proliferation (Sonnenschein and Soto 1999). Under conditions of proliferation such as ductal branching during development of the mammary gland, selected mechanisms are engaged to permit controlled or directed proliferation. In the case of ductal branching, stromal cells respond to estrogen and growth hormone by releasing IGF1, which activates IGF-1R in epithelial cells to promote survival and proliferation (Hinck and Silberstein 2005; Sternlicht, Sunnarborg et al. 2005; Sternlicht 2006). At puberty, epithelial cells respond to estrogen by signaling to the stroma via EGFR to which the stroma replies with proliferative signals via FGFR (Sternlicht, Sunnarborg et al. 2005; Sternlicht 2006). Multiple additional mechanisms of control include proliferation inhibition by TGF-β, which can both directly inhibit proliferation (Francis, Bergsied et al. 2009) and act through stromal cells to stabilize an inhibitory extracellular matrix (Hinck and Silberstein 2005). When mechanisms controlling proliferation are altered, proliferation can occur outside of the normal biological context (Radice, Ferreira-Cornwell et al. 1997; Davies, Platt-Higgins et al. 1999; Ewan, Shyamala et al. 2002; Lanigan, O'Connor et al. 2007; Croce 2008; de Ostrovich, Lambertz et al. 2008).
Uncertainties and Inconsistencies
Mutations are clearly not the only events driving proliferation in mammary gland, particularly in female mammary glands after exposure to a stressor like ionizing radiation where proliferation varies with age and microenvironment (Tang, Fernandez-Garcia et al. 2014). In mammary tissue, stromal state strongly influences the proliferative and metastatic nature of epithelial cells, and mutated epithelial cells alone appear to be insufficient for tumor growth. Stroma exposed to carcinogens can make transplanted unexposed epithelial cells tumorigenic in rats (Maffini, Soto et al. 2004) and transplanted p53 mutant epithelial cells tumorigenic in BALB/c mice (Barcellos-Hoff and Ravani 2000), while neither epithelia exposed to carcinogens nor p53 mutant cells are tumorigenic when transplanted into unexposed animals (Barcellos-Hoff and Ravani 2000; Maffini, Soto et al. 2004). Similarly, post-lactational stroma can make tumor cells more invasive and metastatic than nulliparous stroma (McDaniel, Rumer et al. 2006), and younger and nulliparous stroma makes tumor cells proliferate more than older and multiparous stroma (Maffini, Calabro et al. 2005). Even proliferating tissue and tumors can regress (Haslam and Bern 1977; Purnell 1980), suggesting that proliferation is insufficient for carcinogenesis in some cases.
While mutations increase linearly in response to ionizing radiation or carcinogens, proliferation (or proliferation of stem cell populations) apparently does not (Beuving, Bern et al. 1967; Mukhopadhyay, Costes et al. 2010; Nguyen, Oketch-Rabah et al. 2011; Tang, Fernandez-Garcia et al. 2014). Because we expect only a subset of mutations to affect cell-cycle or proliferation-related genes and because most cells require multiple mutations for proliferation to commence, only a very small number of cells would be expected to proliferate in response to mutation. It is therefore possible that the proliferation typically observed is actually due to a separate mechanism such as the self-renewal of stem-like or senescent-resistant cells and that a delayed mutation-based proliferation is not being measured.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Proliferation increases the likelihood that existing DNA damage will result in mutation and creates new mutations through errors in replication.
It is generally accepted that proliferation increases the risk of mutation and cancer (Preston-Martin, Pike et al. 1990). DNA damage that has not been completely or correctly repaired when a cell undergoes mitosis can be fixed in the genome permanently as a mutation, to be propagated to future daughter cells. Incomplete DNA repair can also cause additional DNA damage when encountered by replicative forks. Therefore, in the presence of any DNA damage (and there is a background rate of damage in addition to any other genotoxic stimuli) mutations will increase with cell division (Kiraly, Gong et al. 2015). Mutation-prone double strand breaks can also arise from replicative stress in hyperplastic cells including hyperplasia arising from excess growth factor stimulation (Gorgoulis, Vassiliou et al. 2005). This relationship between proliferation and mutation is thought to drive a significant portion of the risk of cancer from estrogen exposure since breast cells proliferate in response to estrogen or estrogen plus progesterone and risk increases with cumulative estrogen exposure (Preston-Martin, Pike et al. 1990).
Not all proliferating tissue shows replicative stress and DSBs - tissue with a naturally high proliferative index like colon cells don’t show any sign of damage (Halazonetis, Gorgoulis et al. 2008). Additional factors are therefore required beyond replication for damage and mutation from replicative stress, but replication is essential for the expression of these factors.
Domain of Applicability
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