This is a legacy representation of this AOP. Please see the current version here:
Molly M. Morgan, Brian P. Johnson, David J. Beebe
Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison
Endocrine disrupting chemicals (EDC), particularly estrogen receptor (ER) agonists, are thought to contribute to the incidence of breast cancer. The majority (approximately 75 percent) of breast cancer cases express the estrogen receptor. Both animal and human studies strongly support that activation of the estrogen receptor stimulates breast cancer development and progression. We created the ER-mediated breast cancer AOP to frame how ER activation (the MIE) leads to breast cancer (the AO). For more information regarding the AOP, refer to the Morgan & Johnson et al. (2015) citation.
Activation of the estrogen receptor in breast epithelial cells stimulates genomic and non-genomic changes, which alters epithelial gene expression and subsequent protein production. Consequently, breast epithelial cells experience increased proliferation, decreased apoptosis, dysfunction of mitochondrial dynamics, increased DNA damage, increased cell motility, and increased oxidative stress. These cellular changes translate to a tissue level where ductal hyperplasia and cell invasion is increased.
While breast epithelial cells are the cancer cell type in ER+ adenocarcinomas, other cell types of the microenvironment interact with the AOP. For example, endothelial cells express ER and upon ER activation, undergo gene expression and protein production changes. Consequently, endothelial cell proliferation and migration is increased, leading to increased angiogenesis, which supports the proliferation of breast cancer epithelial cells. While estrogens do not target fibroblasts, adipocytes, or macrophages directly, they become activated as breast cancer progresses. It is not well understood if there is a direct relationship between estrogen signaling and stromal cell activation, however, activated cells stimulate cancer cell proliferation, influence chemical response, increase cell motility, and rearrange the extracellular matrix. Moreover, adipocytes contribute to the AOP through metabolism of testosterone to estrogen, and fibroblasts have been shown to regulate estrogen receptor regulated genes in epithelial cells. Therefore, due to how the breast microenvironment interacts with and stimulates the AOP, we have included activation of these cell types into our framework.
Overall, the ER-mediated breast cancer AOP is a useful framework that can identify both readouts and components of the breast microenvironment that are important in disease progression.
Summary of the AOP
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Molecular Initiating Event
|Molecular Initiating Event||Support for Essentiality|
|Estrogen receptor, Activation||Strong|
|Breast Cancer, N/A|
Relationships Among Key Events and the Adverse Outcome
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Life Stage Applicability
|Not Otherwise Specified||Strong|
|dog||Canis lupus familiaris||Strong||NCBI|
Overall Assessment of the AOP
Applicability of the AOP
Sex. While females have a higher incidence of breast cancer, estrogen-receptor mediated breast cancer can occur in males and females.
Life stages. Breast cancer affects adult women and men. Older adult women have a higher probability of having an ER+ breast cancer (vs. ER-) than younger adult women.
Taxonomic applicability. Breast cancer occurs naturally in humans, cats, and dogs. In vivo studies primarily study breast cancer in mice.
Essentiality of the Key Events
Molecular Initiating Event Summary,
Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.
Weight of Evidence Summary
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.
The weight of evidence for the KERs related to epithelial cells is mostly strong. The KERs between ER activation, motility, and invasion were labeled as a moderate weight of evidence due to discrepancies in the literature regarding whether ER activation decreases motility/invasion, vs. increases motility/invasion. ER activation leading to non-genomic signaling was labeled as moderate due to the limited evidence supporting this KER. For non-epithelial cell types, we labeled the KERs relationship as mostly weak. ER activation has direct effects on endothelial cells as they express ER and several studies have correlated ER activation with increased proliferation, migration, and angiogenesis. Macrophages, fibroblasts, and adipocytes are influenced by and stimulate breast cancer progression, however, the exact correlation between ER activation and these events is still unclear.
Provide an overall discussion of the quantitative information available for this AOP. Support calls for the individual relationships can be included in the Key Event Relationship table above.
Aboussekhra, A. (2011). Role of cancer-associated fibroblasts in breast cancer development and prognosis. Int J Dev Biol, 55(7-9), 841-849. Albini, A., Graf, J., Kitten, G. T., Kleinman, H. K., Martin, G. R., Veillette, A., et al. (1986). 17 beta-estradiol regulates and v-Ha-ras transfection constitutively enhances MCF7 breast cancer cell interactions with basement membrane. Proc Natl Acad Sci U S A, 83(21), 8182-8186. Applanat, M. P., Buteau-Lozano, H., Herve, M. A., & Corpet, A. (2008). Vascular endothelial growth factor is a target gene for estrogen receptor and contributes to breast cancer progression. Adv Exp Med Biol, 617, 437-444. Bailey, S. T., Shin, H., Westerling, T., Liu, X. S., & Brown, M. (2012). Estrogen receptor prevents p53-dependent apoptosis in breast cancer. Proc Natl Acad Sci U S A, 109(44), 18060-18065. Bjornstrom, L., & Sjoberg, M. (2005). Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol, 19(4), 833-842. Bohrer, L. R., & Schwertfeger, K. L. (2012). Macrophages promote fibroblast growth factor receptor-driven tumor cell migration and invasion in a Cxcr2-dependent manner. Mol Cancer Res, 10(10), 1294-1305. Bourdeau, V., Deschenes, J., Metivier, R., Nagai, Y., Nguyen, D., Bretschneider, N., et al. (2004). Genome-wide identification of high-affinity estrogen response elements in human and mouse. Mol Endocrinol, 18(6), 1411-1427. Bracke, M. E., Charlier, C., Bruyneel, E. A., Labit, C., Mareel, M. M., & Castronovo, V. (1994). Tamoxifen restores the E-cadherin function in human breast cancer MCF-7/6 cells and suppresses their invasive phenotype. Cancer Res, 54(17), 4607-4609. Bulun, S. E., Lin, Z., Zhao, H., Lu, M., Amin, S., Reierstad, S., et al. (2009). Regulation of aromatase expression in breast cancer tissue. Ann N Y Acad Sci, 1155, 121-131. Caldon, C. E. (2014). Estrogen Signaling and the DNA Damage Response in Hormone Dependent Breast Cancers. Front Oncol, 4. Calippe, B., Douin-Echinard, V., Delpy, L., Laffargue, M., Lelu, K., Krust, A., et al. (2010). 17Beta-estradiol promotes TLR4-triggered proinflammatory mediator production through direct estrogen receptor alpha signaling in macrophages in vivo. J Immunol, 185(2), 1169-1176. Campbell, L., Emmerson, E., Williams, H., Saville, C. R., Krust, A., Chambon, P., et al. (2014). Estrogen receptor-alpha promotes alternative macrophage activation during cutaneous repair. J Invest Dermatol, 134(9), 2447-2457. Cavalieri, E., Frenkel, K., Liehr, J. G., Rogan, E., & Roy, D. (2000). Estrogens as endogenous genotoxic agents--DNA adducts and mutations. J Natl Cancer Inst Monogr(27), 75-93. Ciocca, D. R., & Fanelli, M. A. (1997). Estrogen receptors and cell proliferation in breast cancer. Trends Endocrinol Metab, 8(8), 313-321. Dabrosin, C., Margetts, P. J., & Gauldie, J. (2003). Estradiol increases extracellular levels of vascular endothelial growth factor in vivo in murine mammary cancer. Int J Cancer, 107(4), 535-540. Dabrosin, C., Palmer, K., Muller, W. J., & Gauldie, J. (2003). Estradiol promotes growth and angiogenesis in polyoma middle T transgenic mouse mammary tumor explants. Breast Cancer Res Treat, 78(1), 1-6. Demirpence, E., Duchesne, M. J., Badia, E., Gagne, D., & Pons, M. (1993). MVLN cells: a bioluminescent MCE-7-derived cell line to study the modulation of estrogenic activity. J Steroid Biochem Mol Biol, 46(3), 355-364. Dirat, B., Bochet, L., Dabek, M., Daviaud, D., Dauvillier, S., Majed, B., et al. (2011). Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res, 71(7), 2455-2465. Doisneau-Sixou, S. F., Sergio, C. M., Carroll, J. S., Hui, R., Musgrove, E. A., & Sutherland, R. L. (2003). Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells. Endocr Relat Cancer, 10(2), 179-186. Felty, Q., & Roy, D. (2005). Estrogen, mitochondria, and growth of cancer and non-cancer cells. [Review]. Journal of Carcinogenesis, 4(1), 1. Felty, Q., Singh, K. P., & Roy, D. (2005). Estrogen-induced G1|[sol]|S transition of G0-arrested estrogen-dependent breast cancer cells is regulated by mitochondrial oxidant signaling. Oncogene, 24(31), 4883-4893. Hall, J. M., Couse, J. F., & Korach, K. S. (2001). The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem, 276(40), 36869-36872. Haslam, S. Z., & Woodward, T. L. (2003). Host microenvironment in breast cancer development: Epithelial-cell–stromal-cell interactions and steroid hormone action in normal and cancerous mammary gland. [Review]. Breast Cancer Research, 5(4), 208. Hayashi, S. I., Eguchi, H., Tanimoto, K., Yoshida, T., Omoto, Y., Inoue, A., et al. (2003). The expression and function of estrogen receptor alpha and beta in human breast cancer and its clinical application. Endocr Relat Cancer, 10(2), 193-202. Improta-Brears, T., Whorton, A. R., Codazzi, F., York, J. D., Meyer, T., & McDonnell, D. P. (1999). Estrogen-induced activation of mitogen-activated protein kinase requires mobilization of intracellular calcium. Proc Natl Acad Sci U S A, 96(8), 4686-4691. Ioachim, E., Charchanti, A., Briasoulis, E., Karavasilis, V., Tsanou, H., Arvanitis, D. L., et al. (2002). Immunohistochemical expression of extracellular matrix components tenascin, fibronectin, collagen type IV and laminin in breast cancer: their prognostic value and role in tumour invasion and progression. Eur J Cancer, 38(18), 2362-2370. Lee, A. V., Jackson, J. G., Gooch, J. L., Hilsenbeck, S. G., Coronado-Heinsohn, E., Osborne, C. K., et al. (1999). Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo. Mol Endocrinol, 13(5), 787-796. Lu, P., Weaver, V. M., & Werb, Z. (2012). The extracellular matrix: A dynamic niche in cancer progression. J Cell Bio, 196(4). Mao, Y., Keller, E. T., Garfield, D. H., Shen, K., & Wang, J. (2013). Stroma Cells in Tumor Microenvironment and Breast Cancer. Cancer Metastasis Rev, 32(0), 303-315. Marchese, S., & Silva, E. (2012). Disruption of 3D MCF-12A breast cell cultures by estrogens--an in vitro model for ER-mediated changes indicative of hormonal carcinogenesis. PLoS One, 7(10), e45767. McDonnell, D. P., & Norris, J. D. (2002). Connections and regulation of the human estrogen receptor. Science, 296(5573), 1642-1644. Mobley, J. A., & Brueggemeier, R. W. (2004). Estrogen receptor-mediated regulation of oxidative stress and DNA damage in breast cancer. Carcinogenesis, 25(1), 3-9. Mor, G., Yue, W., Santen, R. J., Gutierrez, L., Eliza, M., Berstein, L. M., et al. (1998). Macrophages, estrogen and the microenvironment of breast cancer. J Steroid Biochem Mol Biol, 67(5-6), 403-411. Morgan, M. M., Johnson, B. P., Livingston, M. K., Schuler, L. A., Alarid, E. T., Sung, K. E., et al. (2016). Personalized in vitro cancer models to predict therapeutic response: Challenges and a framework for improvement. Pharmacol Ther. Musgrove, E. A., & Sutherland, R. L. (2009). Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer, 9(9), 631-643. Novaro, V., Roskelley, C. D., & Bissell, M. J. (2003). Collagen-IV and laminin-1 regulate estrogen receptor α expression and function in mouse mammary epithelial cells. J Cell Sci, 116(Pt 14), 2975-2986. O'Lone, R., Frith, M. C., Karlsson, E. K., & Hansen, U. (2004). Genomic targets of nuclear estrogen receptors. Mol Endocrinol, 18(8), 1859-1875. Obeid, E., Nanda, R., Fu, Y. X., & Olopade, O. I. (2013). The role of tumor-associated macrophages in breast cancer progression Int J Oncol (Vol. 43, pp. 5-12). OECD. (2012). Proposal for a template and guidance on developing and assessing the completeness of adverse outcome pathways: OECD. Paoletti, C., Muniz, M. C., Thomas, D. G., Griffith, K. A., Kidwell, K. M., Tokudome, N., et al. (2015). Development of circulating tumor cell-endocrine therapy index in patients with hormone receptor-positive breast cancer. Clin Cancer Res, 21(11), 2487-2498. Platet, N., Cathiard, A. M., Gleizes, M., & Garcia, M. (2004). Estrogens and their receptors in breast cancer progression: a dual role in cancer proliferation and invasion. Crit Rev Oncol Hematol, 51(1), 55-67. Provenzano, P. P., Eliceiri, K. W., Campbell, J. M., Inman, D. R., White, J. G., & Keely, P. J. (2006). Collagen reorganization at the tumor-stromal interface facilitates local invasion. [Research article]. BMC Medicine, 4(1), 38. Provenzano, P. P., Inman, D. R., Eliceiri, K. W., Knittel, J. G., Yan, L., Rueden, C. T., et al. (2008). Collagen density promotes mammary tumor initiation and progression. [Research article]. BMC Medicine, 6(1), 11. Saji, S., Kawakami, M., Hayashi, S., Yoshida, N., Hirose, M., Horiguchi, S., et al. (2005). Significance of HDAC6 regulation via estrogen signaling for cell motility and prognosis in estrogen receptor-positive breast cancer. Oncogene, 24(28), 4531-4539. Santen, R. J., Santner, S. J., Pauley, R. J., Tait, L., Kaseta, J., Demers, L. M., et al. (1997). Estrogen production via the aromatase enzyme in breast carcinoma: which cell type is responsible? J Steroid Biochem Mol Biol, 61(3-6), 267-271. Sastre-Serra, J., Nadal-Serrano, M., Pons, D. G., Roca, P., & Oliver, J. (2012). Mitochondrial dynamics is affected by 17beta-estradiol in the MCF-7 breast cancer cell line. Effects on fusion and fission related genes. Int J Biochem Cell Biol, 44(11), 1901-1905. Sastre-Serra, J., Nadal-Serrano, M., Pons, D. G., Valle, A., Oliver, J., & Roca, P. (2015). The Effects of 17β-estradiol on Mitochondrial Biogenesis and Function in Breast Cancer Cell Lines are Dependent on the ERα/ERβ Ratio. Cellular Physiology and Biochemistry, 29(1-2), 261-268. Sastre-Serra, J., Valle, A., Company, M. M., Garau, I., Oliver, J., & Roca, P. (2010). Estrogen down-regulates uncoupling proteins and increases oxidative stress in breast cancer. Free Radic Biol Med, 48(4), 506-512. Sengupta, K., Banerjee, S., Saxena, N., & Banerjee, S. K. (2003). Estradiol-induced vascular endothelial growth factor-A expression in breast tumor cells is biphasic and regulated by estrogen receptor-alpha dependent pathway. Int J Oncol, 22(3), 609-614. Simoncini, T., Mannella, P., Fornari, L., Caruso, A., Varone, G., & Genazzani, A. R. (2004). Genomic and non-genomic effects of estrogens on endothelial cells. Steroids, 69(8-9), 537-542. Simpson, E. R. (2003). Sources of estrogen and their importance. J Steroid Biochem Mol Biol, 86(3-5), 225-230. Soon, P. S., Kim, E., Pon, C. K., Gill, A. J., Moore, K., Spillane, A. J., et al. (2013). Breast cancer-associated fibroblasts induce epithelial-to-mesenchymal transition in breast cancer cells. Endocr Relat Cancer, 20(1), 1-12. Sounni, N. E., & Noel, A. (2013). Targeting the tumor microenvironment for cancer therapy. Clin Chem, 59(1), 85-93. Tan, J., Buache, E., Chenard, M. P., Dali-Youcef, N., & Rio, M. C. (2011). Adipocyte is a non-trivial, dynamic partner of breast cancer cells. Int J Dev Biol, 55(7-9), 851-859. Thompson, E. W., Reich, R., Shima, T. B., Albini, A., Graf, J., Martin, G. R., et al. (1988). Differential regulation of growth and invasiveness of MCF-7 breast cancer cells by antiestrogens. Cancer Res, 48(23), 6764-6768. van Landeghem, A. A., Poortman, J., Nabuurs, M., & Thijssen, J. H. (1985). Endogenous concentration and subcellular distribution of estrogens in normal and malignant human breast tissue. Cancer Res, 45(6), 2900-2906. Wang, T. T., & Phang, J. M. (1995). Effects of estrogen on apoptotic pathways in human breast cancer cell line MCF-7. Cancer Res, 55(12), 2487-2489. Williams, J. A., & Phillips, D. H. (2000). Mammary expression of xenobiotic metabolizing enzymes and their potential role in breast cancer. Cancer Res, 60(17), 4667-4677. Yager, J. D., & Davidson, N. E. (2006). Estrogen carcinogenesis in breast cancer. N Engl J Med, 354(3), 270-282. Yamaguchi, Y. (2007). Microenvironmental regulation of estrogen signals in breast cancer. Breast Cancer, 14(2), 175-181. Yamamoto, M., Hosoda, M., Nakano, K., Jia, S., Hatanaka, K. C., Takakuwa, E., et al. (2014). p53 accumulation is a strong predictor of recurrence in estrogen receptor-positive breast cancer patients treated with aromatase inhibitors. Cancer Sci, 105(1), 81-88. Zhang, X. H., Giuliano, M., Trivedi, M. V., Schiff, R., & Osborne, C. K. (2013). Metastasis dormancy in estrogen receptor-positive breast cancer. Clin Cancer Res, 19(23), 6389-6397. Zheng, S., Huang, J., Zhou, K., Zhang, C., Xiang, Q., Tan, Z., et al. (2011). 17β-Estradiol Enhances Breast Cancer Cell Motility and Invasion via Extra-Nuclear Activation of Actin-Binding Protein Ezrin PLoS One (Vol. 6). Zivadinovic, D., Gametchu, B., & Watson, C. S. (2004). Membrane estrogen receptor-α levels in MCF-7 breast cancer cells predict cAMP and proliferation responses. [Research article]. Breast Cancer Research, 7(1).