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Relationship: 1902

Title

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Increased pro-inflammatory mediators leads to N/A, Breast Cancer

Upstream event

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Increased pro-inflammatory mediators

Downstream event

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N/A, Breast Cancer

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer adjacent Moderate Not Specified
Increased DNA damage leading to increased risk of breast cancer adjacent Moderate Not Specified

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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Pro-inflammatory mediators increase the risk of breast cancer.

Evidence Supporting this KER

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Biological Plausibility is Moderate. Tissue environment is known to be a major factor in carcinogenesis, and inflammatory processes are implicated in the development and invasiveness of breast and other cancers.

Empirical Evidence is Moderate. Interventions to increase inflammatory factors increase the carcinogenic potential of targeted and non-targeted cells. Inflammation is documented at earlier time points than tumorigenesis or invasion- within minutes or hours compared to days to months for carcinogenesis, consistent with an inflammatory mechanism of tumorigenesis and invasion. Inhibition of cytokines, inflammatory signaling pathways, and downstream effectors of inflammation activity prevent transformation, tumorigenesis, and invasion (including EMT and senescence) following IR or stimulation of inflammatory pathways. However, the key event and the adverse outcome differ in their dose-response to ionizing radiation: inflammation does not increase linearly with dose, while breast cancer and invasion does. Uncertainty arises from differences between the CBA/Ca mouse susceptible to leukemia from IR and the BALB/c mouse susceptible to mammary tumors from IR- the former has a pro-inflammatory response while the latter is apparently a mix of anti- and pro-inflammatory. This is a reminder that both pro- and anti-inflammatory factors may contribute to carcinogenesis- further research will be required to identify the context for each.

Biological Plausibility

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Biological Plausibility is Moderate. Tissue environment is known to be a major factor in carcinogenesis, and inflammatory processes are implicated in the development and invasiveness of breast and other cancers. Studies suggest carcinogenic effects of IR extend beyond DNA damage and mutation of directly affected cells (Bouchard, Bouvette et al. 2013; Sridharan, Asaithamby et al. 2015; Barcellos-Hoff and Mao 2016), including indirect effects through exposed stroma of mammary gland (Nguyen, Oketch-Rabah et al. 2011; Nguyen, Fredlund et al. 2013; Illa-Bochaca, Ouyang et al. 2014). Inflammatory reactions offer one possible mechanism. Tumors and tumor cells exhibit features of inflammation, and inflammation is generally understood to promote transformation and tumor progression by supporting multiple hallmarks of cancer including oxidative activity and DNA damage, survival and proliferation, angiogenesis, and invasion and metastasis (Iliopoulos, Hirsch et al. 2009; Hanahan and Weinberg 2011; Esquivel-Velazquez, Ostoa-Saloma et al. 2015).

In photocarcinogenesis, cytokines and inflammatory signaling are implicated in immunosuppression and in promoting DNA damage via RONS (Valejo Coelho, Matos et al. 2016). In addition, inflammation related NF-kB, STAT3, COX2 and prostaglandins are implicated in the development and proliferation of skin cancers (Martens, Seebode et al. 2018).

Multiple cytokines and inflammatory pathways are implicated in mammary tumors and breast cancer.  Cytokines TGF-b and IL6 transform primary human mammospheres and pre-malignant mammary epithelial cell lines in vitro and make them tumorigenic in vivo (Sansone, Storci et al. 2007; Iliopoulos, Hirsch et al. 2009; Nguyen, Oketch-Rabah et al. 2011). IL6 is expressed by breast cancer fibroblasts and by fibroblasts from common sites of breast metastasis (breast, lung, and bone). IL6 is required for the growth and tumor promoting effects of fibroblasts from these sites on ER-positive (MCF-7) cancer cells in vitro and in vivo. IL6 can also promote the expression of IL6 in senescent (skin) fibroblasts and pre-malignant ER- breast epithelial cells (MCF10A). (Sasser, Sullivan et al. 2007; Studebaker, Storci et al. 2008). The growth and invasion-promoting effects of IL6 on primary non-cancer and cancer cell line (MCF-7) mammospheres in vitro depends on the activity of transcription factor NOTCH3, which supports the renewal of stem-like cell populations (Sansone, Storci et al. 2007). The inflammation-related transcription factor NF-kB contributes to mammary tumorigenesis and metastasis in PyVt mice (Connelly, Barham et al. 2011), and NF-kB/IL6/STAT3 activation is essential to mammosphere formation and migration in vitro as well as tumorigenesis from Src-activated or IL6 transformed MCF10 cells (Iliopoulos, Hirsch et al. 2009). The NF-kB/IL6/STAT3 signaling pathway generates cancer stem cells in multiple types of breast cancer cells lines and primary cancer cells (Iliopoulos, Hirsch et al. 2009; Iliopoulos, Jaeger et al. 2010; Iliopoulos, Hirsch et al. 2011) and is also implicated in colon and other cancers (Iliopoulos, Jaeger et al. 2010).

Empirical Evidence

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Empirical Evidence is Moderate. Interventions to increase inflammatory factors increase the carcinogenic potential of targeted and non-targeted cells. Inflammation is documented at earlier time points than tumorigenesis or invasion- within minutes or hours compared to days to months for carcinogenesis, consistent with an inflammatory mechanism of tumorigenesis and invasion. Inhibition of cytokines, inflammatory signaling pathways, and downstream effectors of inflammation activity prevent transformation, tumorigenesis, and invasion (including EMT and senescence) following IR or stimulation of inflammatory pathways. However, the key event and the adverse outcome differ in their dose-response to ionizing radiation: inflammation does not increase linearly with dose, while breast cancer and invasion does. Uncertainty arises from differences between the CBA/Ca mouse susceptible to leukemia from IR and the BALB/c mouse susceptible to mammary tumors from IR- the former has a pro-inflammatory response while the latter is apparently a mix of anti- and pro-inflammatory. This is a reminder that both pro- and anti-inflammatory factors may contribute to carcinogenesis- further research will be required to identify the context for each.

Interventions to increase inflammatory factors in vitro increase the carcinogenic potential of targeted and non-targeted cells. Stimulating inflammatory pathways with TNF-a, TGF-β, or IL6 increases transformation of pre-malignant embryonic fibroblast and breast epithelial cell lines (MCF10, CDβGeo) cells in vitro (Yan, Wang et al. 2006; Iliopoulos, Hirsch et al. 2009; Iliopoulos, Jaeger et al. 2010; Nguyen, Oketch-Rabah et al. 2011) and TGF-β and IL6 promote tumor formation by transplanted pre-malignant (MCF10A) and cancer cell lines (MCF-7, SRC-transformed MCF10A) (Sasser, Sullivan et al. 2007; Studebaker, Storci et al. 2008; Iliopoulos, Hirsch et al. 2009; Iliopoulos, Jaeger et al. 2010; Iliopoulos, Hirsch et al. 2011; Nguyen, Oketch-Rabah et al. 2011). In addition, TGF-β and IL6 promote senescence in fibroblasts (Studebaker, Storci et al. 2008; Liakou, Mavrogonatou et al. 2016) and TGF-b promotes EMT in epithelial cells (Park, Henshall-Powell et al. 2003; Andarawewa, Costes et al. 2011; Iizuka, Sasatani et al. 2017), and senescent fibroblasts and EMT cells support invasion of non-cancer and cancer cells in vitro (Kim, Kim et al. 2004; Andarawewa, Erickson et al. 2007; Sansone, Storci et al. 2007). Most studies used a single dose, but the effects of IL6 on the growth rate of MCF7 cells and of TGF-β on migration and invasion of MCF10A cells are dose-dependent (Kim, Kim et al. 2004; Sasser, Sullivan et al. 2007).

In animal models of carcinogenesis, inflammation is documented at earlier time points than tumorigenesis or invasion- within minutes or hours compared to days to months for carcinogenesis. This temporal concordance is consistent with an inflammatory mechanism of tumorigenesis and invasion. NF-kB activation increases with time and prior to the appearance of mammary tumors in a mouse model of mammary gland tumors (PyVt) (Connelly, Barham et al. 2011). IR increases both inflammatory signaling and tumorigenesis or invasion. Although only one study (Bouchard, Bouvette et al. 2013) measures both key event and adverse outcome in the same experiment, several studies report that inflammatory signals are enriched in IR-induced mammary gland cancers (Nguyen, Oketch-Rabah et al. 2011; Nguyen, Fredlund et al. 2013; Illa-Bochaca, Ouyang et al. 2014), and polymorphisms in inflammatory genes influence susceptibility to intestinal cancer following IR (Elahi, Suraweera et al. 2009).

Inflammation and carcinogenesis do not have the same dose-response to ionizing radiation: inflammatory signals do not always increase linearly with dose, while carcinogenesis does. To our knowledge no studies examine both early inflammation and tumorigenesis or invasion in response to multiple doses of ionizing radiation, so we instead compare the responses reported separately. TGF-β increases with dose in mammary gland (Ehrhart, Segarini et al. 1997) and IL6 and IL8 increase with IR dose in endothelial cells, but other cytokines (IL1, TNF-a) do not (Meeren, Bertho et al. 1997; Natarajan, Gibbons et al. 2007). Studies in cardiac cells and monocytes report a mixture of linear and non-monotonic dose response (El-Saghire, Thierens et al. 2013; Monceau, Meziani et al. 2013), and one study with fractionated low dose (repeated doses of <0.00003 Gy each, totaling 0.06-0.16 Gy) reported an inverse relationship between dose and inflammation (Ebrahimian, Beugnies et al. 2018). In contrast, carcinogenesis increases with IR dose (Tsai, Chuang et al. 2005; Nguyen, Oketch-Rabah et al. 2011). This discrepancy in dose response suggests that for IR, inflammation is not likely to be the sole factor driving carcinogenesis. 

Inhibition of cytokines, inflammatory signaling pathways, and downstream effectors of inflammation activity prevent transformation, tumorigenesis, and invasion (including EMT and senescence) following IR or stimulation of inflammatory pathways. Targeted inhibition of NF-kB activation in mammary epithelium increases tumor latency and decreases tumor burden and metastasis in the PyVT mouse model of mammary carcinogenesis (Connelly, Barham et al. 2011). Inhibition of COX2, IL6, or addition of antioxidants reduces transformation by IR, IL6-expressing fibroblasts, or TNF-a (Bisht, Bradbury et al. 2003; Yan, Wang et al. 2006; Iliopoulos, Hirsch et al. 2009; Iliopoulos, Jaeger et al. 2010; Iliopoulos, Hirsch et al. 2011), and inhibition of IL6 reduces tumor formation by SRC oncogene, IL6-transformed or stimulated cancer cells, and IL6 expressing fibroblasts (Sasser, Sullivan et al. 2007; Studebaker, Storci et al. 2008; Iliopoulos, Hirsch et al. 2009; Iliopoulos, Jaeger et al. 2010; Iliopoulos, Hirsch et al. 2011). Although inhibiting IL6 could not reduce senescence induced by IR in human fetal lung and neonatal foreskin fibroblasts and measured by senescence-associated b-galactosidase (Perrott, Wiley et al. 2017), TGF-β and SMAD inhibitors reduced expression of senescence marker SDC1 induced by IR (Liakou, Mavrogonatou et al. 2016). Antibodies to TGF-β block EMT and invasion induced by IR, and MAPK, MMP, and ERK inhibitors reduce the EMT and mobility or invasion induced by TGF-β (Kim, Kim et al. 2004; Andarawewa, Erickson et al. 2007). Inhibiting NOTCH prevents the invasion of MCF7 cells treated with IL6 (Sansone, Storci et al. 2007).

Most (around 85%) of the evidence linking inflammation with tumorigenesis and invasion is from mammary gland or mammary fibroblasts or epithelial cells. Evidence for inflammation following IR, however, is from a wide range of tissue including endothelia, heart, lung, and includes two studies in mammary gland documenting elevated TGF-β, IL6, and COX2.

Uncertainties and Inconsistencies

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Uncertainty arises from the multifunctional nature of TGF-β, which may be anti- or pro-carcinogenic based on context, and around the contribution of inflammatory macrophages, which can differ based on genetic background. Further research is needed to isolate and identify the critical factors in these responses and their application in mammary gland.

TGF-β can be protective in a developmental context but may increase risk in another context. Increased baseline TGF-β decreases tumor incidence following lower doses of IR (0.1 Gy) in the SPRET outbred mouse, possibly by reducing ductal branching during development and subsequent susceptibility (Zhang, Lo et al. 2015). Conversely, the BALB/c mouse has lower baseline TGF-β during development but is susceptible to mammary tumors after IR, possibly via an elevated TGF-β response to IR. Early (4 hours) after low dose (0.075 Gy) IR these mice have suppressed immune pathways and macrophage response but increased IL6, COX2, and TGF-β pathway activation in mammary gland compared to the tumor-resistant C57BL/6 mouse (Snijders, Marchetti et al. 2012; Bouchard, Bouvette et al. 2013). By 1 week after IR BALB/c mammary glands show TGF-β-dependent inflammation, and by 1 month after IR they show proliferation (Nguyen, Martinez-Ruiz et al. 2011; Snijders, Marchetti et al. 2012). Consistent with this pattern, BALB/c mice that are heterozygous for TGF-β are more resistant to mammary tumorigenesis following IR (Nguyen, Oketch-Rabah et al. 2011). This pattern suggests that TGF-β is associated with inflammation, proliferation, and mammary tumorigenesis in these mice. However, the BALB/c mouse also has a polymorphism in a DNA repair gene associated with IR-induced genomic instability (Yu, Okayasu et al. 2001), making it difficult to distinguish potentially overlapping mechanisms.

Genetically susceptible mouse models offer somewhat conflicting information about the contribution of inflammation to cancer. In the CBA/Ca mouse susceptible to leukemia the macrophage response to IR is pro-inflammatory (M1 type) in contrast to the mammary tumor resistant C57BL/6 mouse, which develops anti-inflammatory M2type pro-phagocytic oxidative macrophages that target apoptotic cells (Lorimore, Coates et al. 2001; Lorimore, Chrystal et al. 2008). In contrast, in the BALB/c mouse susceptible to mammary tumors many inflammatory pathways and macrophages are suppressed early after IR, although there is also evidence of inflammation especially at later points (Nguyen, Martinez-Ruiz et al. 2011; Snijders, Marchetti et al. 2012; Bouchard, Bouvette et al. 2013).  It is possible that the two carcinogenic models represent two different mechanisms of susceptibility.

Finally, inflammation and other stromal factors alone are not sufficient to produce breast cancer. Studies in mice that support the importance of stromal context to IR tumorigenesis used epithelial cells with mutations in a DNA damage response gene p53. These transplant studies irradiate a mammary gland fat pad with epithelial cells removed, and transplant non-irradiated pre-malignant mutant (typically p53 mutant) epithelial cells (Barcellos-Hoff and Ravani 2000; Nguyen, Oketch-Rabah et al. 2011). Similar experiments showing NMU-treated stromal promotion of tumorigenesis use untreated primary epithelial cells sub-cultured repeatedly in vitro where some initiation could have taken place (Maffini, Soto et al. 2004), while in a similar experiment DMBA-treated stroma does not cause tumors from transplanted pre-malignant immortal cells (Medina and Kittrell 2005). This dependence on both stromal context and mutations to DNA damage response is consistent with contemporary ideas about the multi-factorial nature of carcinogenesis.

Quantitative Understanding of the Linkage

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Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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References

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Barcellos-Hoff, M. H. and J. H. Mao (2016). "HZE Radiation Non-Targeted Effects on the Microenvironment That Mediate Mammary Carcinogenesis." Front Oncol 6: 57.

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Bisht, K. S., C. M. Bradbury, et al. (2003). "Inhibition of cyclooxygenase-2 with NS-398 and the prevention of radiation-induced transformation, micronuclei formation and clonogenic cell death in C3H 10T1/2 cells." Int J Radiat Biol 79(11): 879-888.

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