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Event: 1182
Key Event Title
Increase, Cell Proliferation (Epithelial Cells)
Short name
Biological Context
Level of Biological Organization |
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Cellular |
Cell term
Cell term |
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epithelial cell |
Organ term
Key Event Components
Process | Object | Action |
---|---|---|
cell proliferation | increased |
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|
ER activation to breast cancer | KeyEvent | Molly M Morgan (send email) | Open for adoption | |
RONS leading to breast cancer | KeyEvent | Jessica Helm (send email) | Under development: Not open for comment. Do not cite | Under Development |
Increased DNA damage leading to breast cancer | KeyEvent | Jessica Helm (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Life Stages
Sex Applicability
Key Event Description
Proliferation occurs when changes in external signals release inhibitory controls limiting entry into the cell cycle, and oncogenic mutations act via these same pathways to generate abnormal proliferation (Hanahan and Weinberg 2011; Weber, Desai et al. 2017). Inhibitory signals such as contact inhibition or TGF-β (Polyak, Kato et al. 1994; Francis, Bergsied et al. 2009) stabilize the mechanisms limiting entry into the cell cycle. Proliferative signals such as those following progesterone or estrogen (Croce 2008; Weber, Desai et al. 2017) or compensatory proliferation after apoptosis (Fogarty and Bergmann 2017) relieve inhibition and enable cells to enter the cell cycle. Mutations that inactivate inhibitory signals (tumor suppressors) or activate proliferative signals (oncogenes) promote proliferation outside of the normal biological context (Gustin, Karakas et al. 2009; Francis, Chakrabarti et al. 2011; Hanahan and Weinberg 2011; Weber, Desai et al. 2017). Abnormal proliferation is typically met with apoptosis or senescence, so additional mutations or other mechanisms are required to escape these additional levels of control for proliferation to continue indefinitely (Garbe, Bhattacharya et al. 2009; Shay and Wright 2011; Fernald and Kurokawa 2013).
Proliferation increases mutations as DNA damage and replication errors become integrated into the genome (Kiraly, Gong et al. 2015). Proliferation can also promote the expansion of existing cells with proliferative mutations. Genomic mutations favoring further proliferation are positively selected from among the expanded cells, resulting in the accumulation of mutational errors and moving the organism further towards cancer. Different clonal populations can also collaborate to promote growth (Marusyk, Tabassum et al. 2014; Franco, Tyson et al. 2016).
How It Is Measured or Detected
Past cellular proliferation can be measured directly using labels that are incorporated into cells upon cell division (BRDU or cytoplasmic proliferation dyes) or indirectly by measuring a change in population size. Ongoing current proliferation can be quantified by labeling a protein associated with the cell cycle (e.g. Ki67). Methods for measuring proliferation were reviewed in (Romar, Kupper et al. 2016) and summarized in Table 1.
Table 1. Common methods for detecting proliferation
Target |
Name |
Method |
Strengths/Weaknesses |
Past proliferation |
Nucleoside analog incorporation (BRDU) |
Microscopy |
Stable, so can see proliferation from a specific time point onward. Can be used in vivo. BRDU must be labeled with a secondary fluorescent or other label for visualization, so it cannot be measured in living cells. |
Past proliferation |
Cytoplasmic proliferation dyes: carboxyfluorescein diacetate succinimidyl ester (CFSE). |
Microscopy |
Enables quantification of successive cell divisions and differentiation between slowly and rapidly cycling cells. Cells survive analysis, so these dyes can be used as part of ongoing experiments. The dyes are better suited to in vitro experiments. |
Past proliferation |
Cell counting |
Microscopy |
An increase in cell numbers over time could represent proliferation or a decrease in apoptosis. Better suited to in vitro experiments, unless a label can be used to uniquely label a population of cells. |
Ongoing proliferation rate |
Ki67 probe |
Microscopy |
Labels all non-G0 phase proliferating cells. Labeling requires permeabilization so examination terminates the experiment. |