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Increase activation, Nuclear factor kappa B (NF-kB) leads to Antagonism, Estrogen receptor
Key Event Relationship Overview
AOPs Referencing Relationship
|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||Agnes Aggy (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
Upstream event: Increased, NF kB activity
Downstream event: Estrogen receptor, Reduced
Evidence Supporting this KER
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).
-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
No specific uncertainties and inconsistencies reported to the best of our knowledge.
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.
Key events connected by this KER occur within hours of exposure.
Known modulating factors
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
- 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
KER has been observed in humans and animals irrespective of the gender and life stage.
Ali, S., & Coombes, R. C. (2002). Endocrine-responsive breast cancer and strategies for combating resistance. Nature Reviews Cancer, 2(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 Chemistry, 271(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 neoplasia, 5(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 Sciences, 101(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 research, 63(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 Sciences, 97(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 Sciences, 98(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 STKE, 2005(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 cell, 58(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 endocrinology, 418, 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 Endocrinology, 18(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 biology, 35(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 Surgery, 63, 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 cell, 30(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 & development, 9(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. Oncogene, 29(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 biology, 17(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 Chemistry, 274(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 medicine, 3(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 cell, 18(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 Chemistry, 276(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 oncology, 4(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 Research, 14(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. Steroids, 74(6), 535-542.
Shostak, K., & Chariot, A. (2011). NF-κB, stem cells and breast cancer: the links get stronger. Breast Cancer Research, 13(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 therapeutics, 6(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. Apoptosis, 10(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. Oncogene, 17(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 cancer, 97(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 Cancer, 12(1), S37.