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Relationship: 2612

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Increase activation, Nuclear factor kappa B (NF-kB) leads to Antagonism, Estrogen receptor

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. 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

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
DNA damage and mutations leading to Metastatic Breast Cancer adjacent Moderate Moderate Usha Adiga (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Select one or more structured terms 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. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mice Mus sp. High NCBI

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

Upstream event: Increased, NF kB activity

Downstream event: Estrogen receptor, Reduced

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help

Activation NF-κB in breast cancer leads to loss of Estrogen Receptor (ER) expression and Human Epidermal Growth Fac- tor Receptor 2 (HER-2) overexpressed via epidermal growth factor receptor (EGFR) and Mitogen Activated Protein Kinase (MAPK) pathway (Laere et al.,2007). Indeed, the binding of epidermal growth factor (EGF) to its receptor (EGFR) activates NF-B, which most likely contributes to this transcription factor's increased activity in ER negative breast cancer cells (Shostak et al.,2011). Because of constitutive production of cytokines and growth factors, loss of ER function has been linked to constitutive NF-kB activity and hyperactive MAPK, resulting in aggressive, metastatic, hormone-resistant malignancies (Ali et al., 2002). Activation of the progesterone receptor can reduce DNA binding and transcriptional activity by inhibiting NF-B-driven gene expression (Kalkhoven et al., 1996). HER-2 stimulates NF-B via the conventional route, which includes IKK (Merkhofer et al., 2010).

Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility 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 (see page 40 of the User Handbook for further information).   More help

-NF-kB activation in breast cancer has been extensively documented in oestrogen receptor negative (ER) breast tumours and ER breast cancer cell lines, implying a significant inhibitory interaction between both signalling pathways (Biswas et al, 2000, 2001, 2004; Zhou et al, 2005). A rise in both NF-kB DNA-binding activity (Nakshatri et al, 1997) and expression of NF-kB target genes such IL8 coincides with a transition from oestrogen dependence to oestrogen independence in breast cancer, indicating inhibitory cross-talk. The fact that some breast tumours that are resistant to the tumoricidal action of anti-estrogens become sensitised to apoptosis and show a drop in NF-kB activity after treatment with oestrogen supports the inverse relationship between ER and NF-kB activity.

-This shows that oestrogen's proapoptotic actions in these tumours are mediated via NF-kB suppression.

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

No specific uncertainties and inconsistencies reported to the best of our knowledge.

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help

Differential Sensitivity of ER α and ERβ Cells to the NF-kB Inhibitor Go6976. A differential sensitivity to Go6976 by ER α and ERβ breast cancer cells was observed (Holloway et al.,2004). The ER α cells were more sensitive and less viable after treatment with this NF-kB inhibitor. The IC50 (50% killing) by Go6976 was 1 mM for Era of MDA-MB435 and MDA-MB231 breast cancer cells, whereas it was greater than 10 mM for ERa of MCF-7 and T47D or the normal mammary epithelial H16N  cells . At 10 mM Go6976, about 80% of the ERa cells were killed, whereas only 15–30% of ERa and normal H16N cells were sensitive to this compound. The relative resistance of the H16N normal human mammary cells indicates a possible high therapeutic index of Go6976 against ERa cancer cells.

This observation is consistent with the previously observed role of NF-kB as an antiapoptotic agent. FACS analysis demonstrated accumulation of sub-G1 population (67%) in Go6976- treated (48 h at 1 mM) ERa vs. only 10–15% in ERa cells, indicating enhanced apoptotic cell death preferentially of ERa cells caused by this low molecular weight compound.

Time-scale
This sub-section should be used to provide 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?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help

Key events connected by this KER occur within hours of exposure.

Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help

Estradiol has been shown to decrease transcriptional activity and expression of NF-kB in a variety of experimental models (Biswas et al., 2005;Lobanova et al.,2007). Estrogen treatment of MCF-7 or MCF-7/H cells resulted in a significant suppression of NF-kB activity in both cell lines, according to research. The antiestrogen tamoxifen boosted NF-kB activity in the cells, indicating that ER plays a key role in NF-kB down-regulation in both parent and hypoxia-tolerant cells.

-MCF-7/T2H cells were discovered to have a partial tolerance to acute cobalt chloride-induced hypoxia while maintaining their estrogen-independent phenotype. In contrast to the MCF-7/H subline, MCF-7/T2H cells had a non-affected baseline NF-kB level, indicating that estrogens are responsible for NF-kB downregulation (Scherbakov et al., 2009).

Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

- Multiple pathways are implicated in the crosstalk between NF-KB and ER. Through many mechanisms, including collaboration with FOXA1 to strengthen latent ER-binding sites and trigger translation of their synergistic genes, NF-KB directly interacts with the DNA-binding activity of ER (Franco et al. 2015). Furthermore, NF-KB affects ER via interacting with its ER co-activator or co-repressor, which changes ER transcriptional activity (Park et al. 2005). Similar to ER, NF-KB has been reported to have a role as a downstream effector for the growth factor pathway, which is recognized to be involved in both ligand-dependent and non-ligand-dependent ER activation, leading to resistance to a wide range of anti- oestrogen drugs (Zhou et al. 2005a, Sas et al. 2012, Frasor et al. 2015).

-NF-KB is also involved in the anti-apoptotic pathway and immune surveillance systems, both of which have been linked to endocrine resistance (Hu et al. 2015; Lim et al. 2016). Furthermore, NF-KB inhibition of ER activity has been observed. The zinc finger repressor B-lymphocyte-induced maturation protein (BLIMP1), which can bind to the ER promoter area and restrict ER transcription, is triggered by the NFB subunit RelB. (Wang et al. 2009). Increasing data suggests that NF-KB plays an important role in the complexities of the endocrine resistance environment in breast cancer.

-NF-KB and ERS1 mutations in breast cancer patients who are resistant to endocrine therapy

TNF needs NF-KB and FOXA1 to change the breast cancer cell transcriptome by modulating latent ER-binding sites.

Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

KER has been observed in humans and animals irrespective of the gender and life stage.

References

List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help

Ali, S., & Coombes, R. C. (2002). Endocrine-responsive breast cancer and strategies for combating resistance. Nature Reviews Cancer2(2), 101-112.

Kalkhoven, E., Wissink, S., van der Saag, P. T., & van der Burg, B. (1996). Negative Interaction between the RelA (p65) Subunit of NF-κB and the Progesterone Receptor (). Journal of Biological Chemistry271(11), 6217-6224.

Allred, D. C., & Mohsin, S. K. (2000). Biological features of premalignant disease in the human breast. Journal of mammary gland biology and neoplasia5(4), 351-364.

Biswas, D. K., Shi, Q., Baily, S., Strickland, I., Ghosh, S., Pardee, A. B., & Iglehart, J. D. (2004). NF-κB activation in human breast cancer specimens and its role in cell proliferation and apoptosis. Proceedings of the National Academy of Sciences101(27), 10137-10142.

 Biswas, D. K., Martin, K. J., McAlister, C., Cruz, A. P., Graner, E., Dai, S. C., & Pardee, A. B. (2003). Apoptosis caused by chemotherapeutic inhibition of nuclear factor-κB activation. Cancer research63(2), 290-295.

 

Biswas, D. K., Cruz, A. P., Gansberger, E., & Pardee, A. B. (2000). Epidermal growth factor-induced nuclear factor κB activation: a major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells. Proceedings of the National Academy of Sciences97(15), 8542-8547.

Biswas, D. K., Dai, S. C., Cruz, A., Weiser, B., Graner, E., & Pardee, A. B. (2001). The nuclear factor kappa B (NF-κB): a potential therapeutic target for estrogen receptor negative breast cancers. Proceedings of the National Academy of Sciences98(18), 10386-10391.

 Biswas, D. K., Singh, S., Shi, Q., Pardee, A. B., & Iglehart, J. D. (2005). Crossroads of estrogen receptor and NF-κB signaling. Science's STKE2005(288), pe27-pe27. 

Franco, H. L., Nagari, A., & Kraus, W. L. (2015). TNFα signaling exposes latent estrogen receptor binding sites to alter the breast cancer cell transcriptome. Molecular cell58(1), 21-34.

Frasor, J., El-Shennawy, L., Stender, J. D., & Kastrati, I. (2015). NFκB affects estrogen receptor expression and activity in breast cancer through multiple mechanisms. Molecular and cellular endocrinology418, 235-239..

Holloway, J. N., Murthy, S., & El-Ashry, D. (2004). A cytoplasmic substrate of mitogen-activated protein kinase is responsible for estrogen receptor-α down-regulation in breast cancer cells: the role of nuclear factor-κB. Molecular Endocrinology18(6), 1396-1410.

Hu, R., Warri, A., Jin, L., Zwart, A., Riggins, R. B., Fang, H. B., & Clarke, R. (2015). NF-κB signaling is required for XBP1 (unspliced and spliced)-mediated effects on antiestrogen responsiveness and cell fate decisions in breast cancer. Molecular and cellular biology35(2), 379-390.

Manginstar, C., Islam, A. A., Sampepajung, D., Hamdani, W., Bukhari, A., Syamsu, S. A., ... & Faruk, M. (2021). The relationship between NFKB, HER2, ER expression and anthracycline-based neoadjuvan chemotherapy response in local advanced stadium breast cancer: A cohort study in Eastern Indonesia. Annals of Medicine and Surgery63, 102164.

Lim, S. O., Li, C. W., Xia, W., Cha, J. H., Chan, L. C., Wu, Y., ... & Hung, M. C. (2016). Deubiquitination and stabilization of PD-L1 by CSN5. Cancer cell30(6), 925-939.

Lobanova, Y. S., Scherbakov, A. M., Shatskaya, V. A., & Krasil’nikov, M. A. (2007). Mechanism of estrogen-induced apoptosis in breast cancer cells: role of the NF-κB signaling pathway. Biochemistry (moscow)72(3), 320-327.

McCarthy, S. A., Samuels, M. L., Pritchard, C. A., Abraham, J. A., & McMahon, M. (1995). Rapid induction of heparin-binding epidermal growth factor/diphtheria toxin receptor expression by Raf and Ras oncogenes. Genes & development9(16), 1953-1964.

Merkhofer, E. C., Cogswell, P., & Baldwin, A. S. (2010). Her2 activates NF-κB and induces invasion through the canonical pathway involving IKKα. Oncogene29(8), 1238-1248.

Nakshatri, H., Bhat-Nakshatri, P., Martin, D. A., Goulet Jr, R. J., & Sledge Jr, G. W. (1997). Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Molecular and cellular biology17(7), 3629-3639.

Norris, J. L., & Baldwin, A. S. (1999). Oncogenic Ras enhances NF-κB transcriptional activity through Raf-dependent and Raf-independent mitogen-activated protein kinase signaling pathways. Journal of Biological Chemistry274(20), 13841-13846.

Osako, T., Nishimura, R., Okumura, Y., Toyozumi, Y., & Arima, N. (2012). Predictive significance of the proportion of ER-positive or PgR-positive tumor cells in response to neoadjuvant chemotherapy for operable HER2-negative breast cancer. Experimental and therapeutic medicine3(1), 66-71.

Park, K. J., Krishnan, V., O’Malley, B. W., Yamamoto, Y., & Gaynor, R. B. (2005). Formation of an IKKα-dependent transcription complex is required for estrogen receptor-mediated gene activation. Molecular cell18(1), 71-82.

Pearson, G., English, J. M., White, M. A., & Cobb, M. H. (2001). ERK5 and ERK2 cooperate to regulate NF-κB and cell transformation. Journal of Biological Chemistry276(11), 7927-7931.

Sampepajung, E., Hamdani, W., Sampepajung, D., & Prihantono, P. (2021). Overexpression of NF-kB as a predictor of neoadjuvant chemotherapy response in breast cancer. Breast Disease, (Preprint), 1-9.

Sarkar, D. K., Jana, D., Patil, P. S., Chaudhari, K. S., Chattopadhyay, B. K., Chikkala, B. R., ... & Chowdhary, P. (2013). Role of NF-κB as a prognostic marker in breast cancer: a pilot study in Indian patients. Indian journal of surgical oncology4(3), 242-247.

Sas, L., Lardon, F., Vermeulen, P. B., Hauspy, J., Van Dam, P., Pauwels, P., ... & Van Laere, S. J. (2012). The interaction between ER and NFκB in resistance to endocrine therapy. Breast Cancer Research14(4), 1-14.

Scherbakov, A. M., Lobanova, Y. S., Shatskaya, V. A., & Krasil’nikov, M. A. (2009). The breast cancer cells response to chronic hypoxia involves the opposite regulation of NF-kB and estrogen receptor signaling. Steroids74(6), 535-542.

Shostak, K., & Chariot, A. (2011). NF-κB, stem cells and breast cancer: the links get stronger. Breast Cancer Research13(4), 1-7.

Singh, S., Shi, Q., Bailey, S. T., Palczewski, M. J., Pardee, A. B., Iglehart, J. D., & Biswas, D. K. (2007). Nuclear factor-κB activation: a molecular therapeutic target for estrogen receptor–negative and epidermal growth factor receptor family receptor–positive human breast cancer. Molecular cancer therapeutics6(7), 1973-1982.

Song, R. D., Zhang, Z., Mor, G., & Santen, R. J. (2005). Down-regulation of Bcl-2 enhances estrogen apoptotic action in long-term estradiol-depleted ER+ breast cancer cells. Apoptosis10(3), 667-678.

Troppmair, J., Hartkamp, J., & Rapp, U. R. (1998). Activation of NF-κB by oncogenic Raf in HEK 293 cells occurs through autocrine recruitment of the stress kinase cascade. Oncogene17(6), 685-690.

Van Laere, S. J., Van der Auwera, I., Van den Eynden, G. G., Van Dam, P., Van Marck, E. A., Vermeulen, P. B., & Dirix, L. Y. (2007). NF-κB activation in inflammatory breast cancer is associated with oestrogen receptor downregulation, secondary to EGFR and/or ErbB2 overexpression and MAPK hyperactivation. British journal of cancer97(5), 659-669.

Wang, X., & Belguise, K. (2009). O’ Neill, CF, Sanchez-Morgan, N. Romagnoli, M., Eddy, SF, Mineva, ND, Yu, Z., Min, C., Trinkaus-Randall, V. et al, 3832-3844.

Zhou, Y., Eppenberger-Castori, S., Eppenberger, U., & Benz, C. C. (2005). The NFkB pathway and endocrine-resistant breast cancer. Endocrine Related Cancer12(1), S37.