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Predictive features of ligand-specific signaling through the estrogen receptor.

Nwachukwu JC, Srinivasan S, Zheng Y, Wang S, Min J, Dong C, Liao Z, Nowak J, Wright NJ, Houtman R, Carlson KE, Josan JS, Elemento O, Katzenellenbogen JA, Zhou HB, Nettles KW
Mol Syst Biol 12 864 (2016)

Cited: 23 times
EuropePMC logo PMID: 27107013

Abstract

Some estrogen receptor-α (ERα)-targeted breast cancer therapies such as tamoxifen have tissue-selective or cell-specific activities, while others have similar activities in different cell types. To identify biophysical determinants of cell-specific signaling and breast cancer cell proliferation, we synthesized 241 ERα ligands based on 19 chemical scaffolds, and compared ligand response using quantitative bioassays for canonical ERα activities and X-ray crystallography. Ligands that regulate the dynamics and stability of the coactivator-binding site in the C-terminal ligand-binding domain, called activation function-2 (AF-2), showed similar activity profiles in different cell types. Such ligands induced breast cancer cell proliferation in a manner that was predicted by the canonical recruitment of the coactivators NCOA1/2/3 and induction of the GREB1 proliferative gene. For some ligand series, a single inter-atomic distance in the ligand-binding domain predicted their proliferative effects. In contrast, the N-terminal coactivator-binding site, activation function-1 (AF-1), determined cell-specific signaling induced by ligands that used alternate mechanisms to control cell proliferation. Thus, incorporating systems structural analyses with quantitative chemical biology reveals how ligands can achieve distinct allosteric signaling outcomes through ERα.

Articles - 5dks mentioned but not cited (2)

  1. Predictive features of ligand-specific signaling through the estrogen receptor. Nwachukwu JC, Srinivasan S, Zheng Y, Wang S, Min J, Dong C, Liao Z, Nowak J, Wright NJ, Houtman R, Carlson KE, Josan JS, Elemento O, Katzenellenbogen JA, Zhou HB, Nettles KW. Mol Syst Biol 12 864 (2016)
  2. Pocket similarity identifies selective estrogen receptor modulators as microtubule modulators at the taxane site. Lo YC, Cormier O, Liu T, Nettles KW, Katzenellenbogen JA, Stearns T, Altman RB. Nat Commun 10 1033 (2019)


Reviews citing this publication (2)

  1. Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance. Katzenellenbogen JA, Mayne CG, Katzenellenbogen BS, Greene GL, Chandarlapaty S. Nat Rev Cancer 18 377-388 (2018)
  2. Role for Growth Regulation by Estrogen in Breast Cancer 1 (GREB1) in Hormone-Dependent Cancers. Cheng M, Michalski S, Kommagani R. Int J Mol Sci 19 E2543 (2018)

Articles citing this publication (19)

  1. Structural and Molecular Mechanisms of Cytokine-Mediated Endocrine Resistance in Human Breast Cancer Cells. Stender JD, Nwachukwu JC, Kastrati I, Kim Y, Strid T, Yakir M, Srinivasan S, Nowak J, Izard T, Rangarajan ES, Carlson KE, Katzenellenbogen JA, Yao XQ, Grant BJ, Leong HS, Lin CY, Frasor J, Nettles KW, Glass CK. Mol Cell 65 1122-1135.e5 (2017)
  2. Full antagonism of the estrogen receptor without a prototypical ligand side chain. Srinivasan S, Nwachukwu JC, Bruno NE, Dharmarajan V, Goswami D, Kastrati I, Novick S, Nowak J, Cavett V, Zhou HB, Boonmuen N, Zhao Y, Min J, Frasor J, Katzenellenbogen BS, Griffin PR, Katzenellenbogen JA, Nettles KW. Nat Chem Biol 13 111-118 (2017)
  3. Systems Structural Biology Analysis of Ligand Effects on ERα Predicts Cellular Response to Environmental Estrogens and Anti-hormone Therapies. Nwachukwu JC, Srinivasan S, Bruno NE, Nowak J, Wright NJ, Minutolo F, Rangarajan ES, Izard T, Yao XQ, Grant BJ, Kojetin DJ, Elemento O, Katzenellenbogen JA, Nettles KW. Cell Chem Biol 24 35-45 (2017)
  4. Origin of an ancient hormone/receptor couple revealed by resurrection of an ancestral estrogen. Markov GV, Gutierrez-Mazariegos J, Pitrat D, Billas IML, Bonneton F, Moras D, Hasserodt J, Lecointre G, Laudet V. Sci Adv 3 e1601778 (2017)
  5. Tyrosine phosphorylation regulates ERβ ubiquitination, protein turnover, and inhibition of breast cancer. Yuan B, Cheng L, Gupta K, Chiang HC, Gupta HB, Sareddy GR, Wang D, Lathrop K, Elledge R, Wang P, McHardy S, Vadlamudi R, Curiel TJ, Hu Y, Ye Q, Li R. Oncotarget 7 42585-42597 (2016)
  6. Estrogen-induced transcription at individual alleles is independent of receptor level and active conformation but can be modulated by coactivators activity. Stossi F, Dandekar RD, Mancini MG, Gu G, Fuqua SAW, Nardone A, De Angelis C, Fu X, Schiff R, Bedford MT, Xu W, Johansson HE, Stephan CC, Mancini MA. Nucleic Acids Res 48 1800-1810 (2020)
  7. ESR1 Mutations Associated With Estrogen Insensitivity Syndrome Change Conformation of Ligand-Receptor Complex and Altered Transcriptome Profile. Li Y, Hamilton KJ, Perera L, Wang T, Gruzdev A, Jefferson TB, Zhang AX, Mathura E, Gerrish KE, Wharey L, Martin NP, Li JL, Korach KS. Endocrinology 161 bqaa050 (2020)
  8. Dual functional small molecule fluorescent probes for image-guided estrogen receptor-specific targeting coupled potent antiproliferative potency for breast cancer therapy. Yang L, Hu Z, Luo J, Tang C, Zhang S, Ning W, Dong C, Huang J, Liu X, Zhou HB. Bioorg Med Chem 25 3531-3539 (2017)
  9. Dual-mechanism estrogen receptor inhibitors. Min J, Nwachukwu JC, Min CK, Njeri JW, Srinivasan S, Rangarajan ES, Nettles CC, Sanabria Guillen V, Ziegler Y, Yan S, Carlson KE, Hou Y, Kim SH, Novick S, Pascal BD, Houtman R, Griffin PR, Izard T, Katzenellenbogen BS, Katzenellenbogen JA, Nettles KW. Proc Natl Acad Sci U S A 118 e2101657118 (2021)
  10. Rational design and optimization of selenophenes with basic side chains as novel potent selective estrogen receptor modulators (SERMs) for breast cancer therapy. Luo J, Hu Z, Xiao Y, Yang T, Dong C, Huang J, Zhou HB. Medchemcomm 8 1485-1497 (2017)
  11. Chemical systems biology reveals mechanisms of glucocorticoid receptor signaling. Bruno NE, Nwachukwu JC, Srinivasan S, Nettles CC, Izard T, Jin Z, Nowak J, Cameron MD, Boregowda SV, Phinney DG, Elemento O, Liu X, Ortlund EA, Houtman R, Stavreva DA, Hager GL, Kamenecka TM, Kojetin DJ, Nettles KW. Nat Chem Biol 17 307-316 (2021)
  12. Nonsteroidal ecdysone receptor agonists use a water channel for binding to the ecdysone receptor complex EcR/USP. Browning C, McEwen AG, Mori K, Yokoi T, Moras D, Nakagawa Y, Billas IML. J Pestic Sci 46 88-100 (2021)
  13. Oxabicycloheptene Sulfonate Protects Against β-Amyloid-induced Toxicity by Activation of PI3K/Akt and ERK Signaling Pathways Via GPER1 in C6 Cells. Deng LJ, Cheng C, Wu J, Wang CH, Zhou HB, Huang J. Neurochem Res 42 2246-2256 (2017)
  14. Discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors. Masuya T, Iwamoto M, Liu X, Matsushima A. Sci Rep 9 9954 (2019)
  15. Exploring the Structural Compliancy versus Specificity of the Estrogen Receptor Using Isomeric Three-Dimensional Ligands. Sharma N, Carlson KE, Nwachukwu JC, Srinivasan S, Sharma A, Nettles KW, Katzenellenbogen JA. ACS Chem Biol 12 494-503 (2017)
  16. Quality Control for Single Cell Imaging Analytics Using Endocrine Disruptor-Induced Changes in Estrogen Receptor Expression. Stossi F, Singh PK, Mistry RM, Johnson HL, Dandekar RD, Mancini MG, Szafran AT, Rao AU, Mancini MA. Environ Health Perspect 130 27008 (2022)
  17. Human Estrogen Receptor Alpha Antagonists, Part 3: 3-D Pharmacophore and 3-D QSAR Guided Brefeldin A Hit-to-Lead Optimization toward New Breast Cancer Suppressants. Kurtanović N, Tomašević N, Matić S, Proia E, Sabatino M, Antonini L, Mladenović M, Ragno R. Molecules 27 2823 (2022)
  18. Perfluorinated compounds binding to estrogen receptor of different species: a molecular dynamic modeling. Qu K, Song J, Zhu Y, Liu Y, Zhao C. J Mol Model 25 1 (2018)
  19. Unconventional isoquinoline-based SERMs elicit fulvestrant-like transcriptional programs in ER+ breast cancer cells. Hancock GR, Young KS, Hosfield DJ, Joiner C, Sullivan EA, Yildiz Y, Lainé M, Greene GL, Fanning SW. NPJ Breast Cancer 8 130 (2022)


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