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Antagonism, Estrogen receptor leads to EMT
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||High||High||Usha Adiga (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|Not Otherwise Specified||Not Specified|
Key Event Relationship Description
Upstream event: Decreased, Estrogen receptor activity
Downstream event: EMT, Increased
Evidence Supporting this KER
Estrogen/ERa signaling maintains an epithelial phenotype and suppresses EMT.ERa signaling promotes proliferation and epithelial differentiation and opposes EMT. ERa activated by E2 inhibits TGF-b signaling and cytokine signaling through Smad and NF-kB, respectively, both of which promote EMT. EMT-related transcription factors and microRNAs are likewise suppressed by ERa signalling. This anti-EMT stance is thought to be a major component in luminal A breast cancer's low spreading potential and excellent prognosis. ERa signalling, on the other hand, promotes the proliferation and survival of ERa-positive breast cancer cells by increasing cell cycle and anti-apoptotic gene expression. Furthermore, because GATA3 is a marker for luminal progenitor cell development and both GATA3 and FOXA1 are cofactors that affect ERa signalling and activity, ERa signalling interacts with luminal-related transcription factors GATA3 and FOXA1 to promote an epithelial phenotype. These elements work together to enhance cell–cell adhesion, basolateral polarity, and low motility in epithelial tissues.
E2/ERa signalling, in part through transcriptional activation of luminal/epithelial-related transcription factors, promotes the development of mammary epithelia along a luminal/epithelial lineage. GATA3 and ERa both promote each other (Eeckhoute et al.,2007). In normal breast epithelia, GATA3 is needed for luminal differentiation(Kouros-Mehr et al.,2008) and GATA3 and ERa control many of the same genes (Wilson et al.,2008). In mice, forcing GATA3 expression in mesenchymal breast cancer cells produces mesenchymal–epithelial transition (MET), a reversible mechanism analogous to EMT, and prevents tumour metastasis (Yan et al.,2010). Another ERa-interacting transcription factor, FOXA1, is essential for luminal lineage in mammary epithelia and stimulates ductal development in mice (Bernardo et al.,2010). FOXA1 enhances ERa gene expression by increasing the accessibility of estrogen-response regions for ERa binding (Nakshatri et al., 2009). In breast cancer cells, on the other hand, E2 appears to increase FOXA1 expression. Importantly, ERa, FOXA1, and GATA3 are all positive breast cancer prognostic factors(Nakshatri et al.,2009).
ERa signalling enhances primary lesion formation (and therefore is mitogenic), but it can control the EMT process (and thus is anti-metastatic) up to a point. Signaling pathways that lead to EMT are antagonised by E2/ERa signalling. TGF-b, for example, has been demonstrated to generate EMT in human mammary epithelial cells, and overexpression of the EMT-inducing protein Snail boosted TGF-b signalling and invasiveness while decreasing adhesion and ERa expression in MCF-7 cells (Taylor et al.,2010). TGF-b has an anti-estrogen impact on MCF-7 cells. Smad2/3 and the Smad-selective E3 ubiquitin ligase Smurf create a ternary complex with ERa, which enhances the proteosomal degradation of Smad proteins, according to Ito et al (Ito et al.,2010).
Uncertainties and Inconsistencies
No specific Uncertainties and Inconsistencies noted to the best of our knowledge.
- Endogenous ER silencing causes EMT in ER-positive breast cancer cells.
ER-positive MCF-7 cells were infected with ER shRNA lentiviral particles and stable clones were selected with puromycin (optimal dose of 0.8 g/mL) to knockdown ER gene expression (Zheng et al.,2014).
-When the number of cell passages was increased following infection, the expression of ER was gradually knocked down.
-ER gene expression was decreased by roughly 25% four passages after infection compared to control lentiviral particles transfected cells (MCF-7/c cells). The ER gene expression was lowered even more in the following passage (passage 5 post-infection) (by around 50% compared to MCF-7/c cells). In passage 7, a significant reduction in ER gene expression (about 75–80%) was seen, along with a distinct transition of cells from an epithelial to a mesenchymal phenotype.
- When MCF-7 cells reach confluency, they develop as closely packed colonies that produce sheet-like monolayer structures. Stable clones from stage 7 post-infection, on the other hand, grew as more elongated individual cells rather than tight clusters, with a spindle-like shape. For stable clones with a distinct mesenchymal character, a very substantial down-regulation of ER gene expression (above 99 percent) was found from passage 10 and beyond. MCF-7/SP10+ was given to these cells to emphasise the stable transfection (S) and passage 10 or more (P10+). The substantial down-regulation of ERa was confirmed by immunofluorescence and Western blot analysis of the same stable clones (MCF-7/ SP10 + cells).
Downstream key event occurs within hours of the occurrence of the upstream key event.
Known modulating factors
Tumour characteristics and heterogeneity, biological changes of tumour progression and interacting molecules, all of which can influence the degree of hormone responsiveness in a particular individual with hormone receptor-positive breast cancer.
Known Feedforward/Feedback loops influencing this KER
EMT is inhibited by ERa, and microRNAs either promote or inhibit EMT . These findings raise the question of whether microRNAs have a role in the control of EMT by targeting ERa mRNA. The large (>4000 nt) 30 untranslated region (30-UTR) of human ERa mRNA, as well as results that particular microRNAs are differentially expressed between ERa-positive and ERa-negative breast tumours , suggest the possibility of microRNA-mediated control of human ERa mRNA(Adams et al.,2008).
Pro-metastatic/anti-proliferative (miR-206), pro-metastatic/pro-proliferative (miR-221/222), and anti-proliferative/anti-metastatic (miR-221/223) ERa-targeting microRNAs (miR-130a, miR-145). MiR-17/92 appears to be prometastatic, although it is implicated in several feedback loops, which could make miR-17/92's expression and effects on proliferation extremely reliant on the microenvironment as well as the genetic and epigenetic background.
Accurate identification of micro-RNAs that contribute significantly to a particular pathway (such as EMT) within breast cancers in situ is one hurdle. MicroRNAs have hundreds of potential targets, and in vivo studies will be needed to identify physiologically important targets in the context of breast cancer, as well as to develop effective treatments for breast cancer that involve manipulating microRNA expression levels and identifying off-target effects. (Adams et al.,2007;Zhao et al.,2008;Leva et al.,2010;Stinson et al.,2011;Acunzo et al.,2011;Castellano et al.,2009).
Domain of Applicability
Humans and animals with no specific gender or life stage specificity.
Acunzo, M., Visone, R., Romano, G., Veronese, A., Lovat, F., Palmieri, D., ... & Croce, C. M. (2012). miR-130a targets MET and induces TRAIL-sensitivity in NSCLC by downregulating miR-221 and 222. Oncogene, 31(5), 634-642.
Adams, B. D., Guttilla, I. K., & White, B. A. (2008, November). Involvement of microRNAs in breast cancer. In Seminars in reproductive medicine (Vol. 26, No. 06, pp. 522-536). © Thieme Medical Publishers.
Adams, B. D., Furneaux, H., & White, B. A. (2007). The micro-ribonucleic acid (miRNA) miR-206 targets the human estrogen receptor-α (ERα) and represses ERα messenger RNA and protein expression in breast cancer cell lines. Molecular endocrinology, 21(5), 1132-1147.
Al Saleh, S., Al Mulla, F., & Luqmani, Y. A. (2011). Estrogen receptor silencing induces epithelial to mesenchymal transition in human breast cancer cells. PloS one, 6(6), e20610.
Bernardo, G. M., Lozada, K. L., Miedler, J. D., Harburg, G., Hewitt, S. C., Mosley, J. D., ... & Keri, R. A. (2010). FOXA1 is an essential determinant of ERα expression and mammary ductal morphogenesis. Development, 137(12), 2045-2054.
Bouris, P., Skandalis, S. S., Piperigkou, Z., Afratis, N., Karamanou, K., Aletras, A. J., ... & Karamanos, N. K. (2015). Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells. Matrix Biology, 43, 42-60.
Castellano, L., Giamas, G., Jacob, J., Coombes, R. C., Lucchesi, W., Thiruchelvam, P., ... & Stebbing, J. (2009). The estrogen receptor-α-induced microRNA signature regulates itself and its transcriptional response. Proceedings of the National Academy of Sciences, 106(37), 15732-15737.
Di Leva, G., Gasparini, P., Piovan, C., Ngankeu, A., Garofalo, M., Taccioli, C., ... & Croce, C. M. (2010). MicroRNA cluster 221-222 and estrogen receptor α interactions in breast cancer. JNCI: Journal of the National Cancer Institute, 102(10), 706-721.
Eeckhoute, J., Keeton, E. K., Lupien, M., Krum, S. A., Carroll, J. S., & Brown, M. (2007). Positive cross-regulatory loop ties GATA-3 to estrogen receptor α expression in breast cancer. Cancer research, 67(13), 6477-6483.
Ito, I., Hanyu, A., Wayama, M., Goto, N., Katsuno, Y., Kawasaki, S., ... & Yanagisawa, J. (2010). Estrogen inhibits transforming growth factor β signaling by promoting Smad2/3 degradation. Journal of biological chemistry, 285(19), 14747-14755.
Kouros-Mehr, H., Kim, J. W., Bechis, S. K., & Werb, Z. (2008). GATA-3 and the regulation of the mammary luminal cell fate. Current opinion in cell biology, 20(2), 164-170.
Lin, H. Y., Liang, Y. K., Dou, X. W., Chen, C. F., Wei, X. L., Zeng, D., ... & Zhang, G. J. (2018). Notch3 inhibits epithelial–mesenchymal transition in breast cancer via a novel mechanism, upregulation of GATA-3 expression. Oncogenesis, 7(8), 1-15.
Liu, Y., Liu, R., Fu, P., Du, F., Hong, Y., Yao, M., ... & Zheng, S. (2015). N1-Guanyl-1, 7-diaminoheptane sensitizes estrogen receptor negative breast cancer cells to doxorubicin by preventing epithelial-mesenchymal transition through inhibition of eukaryotic translation initiation factor 5A2 activation. Cellular Physiology and Biochemistry, 36(6), 2494-2503.
Nakshatri, H., & Badve, S. (2009). FOXA1 in breast cancer. Expert reviews in molecular medicine, 11.
Stinson, S., Lackner, M. R., Adai, A. T., Yu, N., Kim, H. J., O’Brien, C., ... & Dornan, D. (2011). TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer. Science signaling, 4(177), ra41-ra41.
Taylor, M. A., Parvani, J. G., & Schiemann, W. P. (2010). The pathophysiology of epithelial-mesenchymal transition induced by transforming growth factor-β in normal and malignant mammary epithelial cells. Journal of mammary gland biology and neoplasia, 15(2), 169-190.
Wilson, B. J., & Giguère, V. (2008). Meta-analysis of human cancer microarrays reveals GATA3 is integral to the estrogen receptor alpha pathway. Molecular cancer, 7(1), 1-8.
Wik, E., Ræder, M. B., Krakstad, C., Trovik, J., Birkeland, E., Hoivik, E. A., ... & Salvesen, H. B. (2013). Lack of estrogen receptor-α is associated with epithelial–mesenchymal transition and PI3K alterations in endometrial carcinoma. Clinical Cancer Research, 19(5), 1094-1105.
Yan, W., Cao, Q. J., Arenas, R. B., Bentley, B., & Shao, R. (2010). GATA3 inhibits breast cancer metastasis through the reversal of epithelial-mesenchymal transition. Journal of Biological Chemistry, 285(18), 14042-14051.
Ye, Y., Xiao, Y., Wang, W., Yearsley, K., Gao, J. X., Shetuni, B., & Barsky, S. H. (2010). ERα signaling through slug regulates E-cadherin and EMT. Oncogene, 29(10), 1451-1462.
Zeng, Q., Zhang, P., Wu, Z., Xue, P., Lu, D., Ye, Z., ... & Yan, X. (2014). Quantitative proteomics reveals ER-α involvement in CD146-induced epithelial-mesenchymal transition in breast cancer cells. Journal of proteomics, 103, 153-169.
Zhao, J. J., Lin, J., Yang, H., Kong, W., He, L., Ma, X., ... & Cheng, J. Q. (2008). MicroRNA-221/222 negatively regulates estrogen receptorα and is associated with tamoxifen resistance in breast cancer. Journal of Biological Chemistry, 283(45), 31079-31087.