405© Springer Nature Switzerland AG 2019 X. Zhang (ed.), Estrogen Receptor and Breast Cancer, Cancer Drug Discovery and Development, https://doi.org/10.1007/978-3-319-99350-8

Appendix: Photo Gallery

406

Photo Gallery Captions:

1. Charles Huggins and Elwood Jensen, circa 1975 2. Elwood Jensen at the Ben May Laboratory for Cancer Research, University of

Chicago 3. Elwood Jensen (third from right) works on a National Defense Research

Council project at the Department of Chemistry, University of Chicago, 1944 4. Elwood Jensen (middle) at the Summit of Mountain Matterhorn, Aug 18, 1947 5. Elwood Jensen at the University of Cincinnati College of Medicine, 2004 6. Elwood Jensen’s 2004 Albert Lasker Award at Henry R. Winkler Center for the

History of the Health Professions, University of Cincinnati’s Donald C. Harrison Health Sciences Library

7. Bert O’Malley (third from right) and pioneers of the field of hormone action in their early days

8. William McGuire (middle, front row), C. Kent Osborne (second from left, back row), and medical oncology faculty, University of Texas Health Sciences Center at San Antonio, 1980

9. Jensen Symposium banquet at the University of Cincinnati, 2003 10. David Moore, Tom Burris, Jan-Åke Gustafsson, and Geoffrey Greene, 2003 11. Elwood Jensen, Bert O’Malley, and Sohaib Khan, 2003 12. Jack Gorski, Ken Korach, and Elwood Jensen, 2003 13. Lee Kraus (middle) with John and Benita Katzenellenbogen at Endocrine

Society meeting, 2014 14. Ken Nephew, Elwood Jensen, and Sohaib Khan at the Midwest Regional

Molecular Endocrinology Conference, Indiana University, 2004 15. Robert G. Roeder, Joanne Masin, and Xiaoting Zhang at Rockefeller University,

2002 16. Robert G.  Roeder and Xiaoting Zhang at the Jensen Symposium on Breast

Cancer 2016, University of Cincinnati 17. Drs. Xiaoyong Fu, Rachel Schiff, Jamunarani Veeraraghavan, C. Kent Osborne,

and Carmine De Angelis at Baylor College of Medicine 18. Tomás Reinert and Matthew Ellis at Washington University, St. Louis, 2014 19. Drs. Jun-lin Guan, Xiaoting Zhang, Craig Jordan, and Jeff Rosen with com-

munity advocate leaders Eileen Barret and Carrie Hayden at a Jensen Symposium outreach event, Queen City Club, Cincinnati, 2016

20. Nira Ben-Jonathan at the Vontz Center for Molecular Studies, University of Cincinnati

21. Christoforos Thomas at University of Houston 22. Balkees Abderrahman at The University of Texas MD Anderson Cancer Center 23. Group photo of Midwest Regional Molecular Endocrinology Conference,

Indiana University, 2004 24. Group photo of Midwest Regional Molecular Endocrinology Conference,

University of Cincinnati, 2002 25. Jensen Symposium Speakers’ Dinner at the Celestial, Cincinnati, 2009 26. Jensen Symposium on Breast Cancer speakers’ dinner at Bell Event Centre,

Cincinnati, 2016

Appendix: Photo Gallery

407© Springer Nature Switzerland AG 2019 X. Zhang (ed.), Estrogen Receptor and Breast Cancer, Cancer Drug Discovery and Development, https://doi.org/10.1007/978-3-319-99350-8

AAACR, 179Abemaciclib, 229, 231, 381, 383, 384, 390Acetylation, 53Activation function 1 (AF1), 50Adenocarcinoma, 22, 35Adjuvant endocrine therapy

aromatase inhibitor, 224, 225breast cancer, 223CTS5, 223ovarian function suppression, 221postmenopausal women, 221, 222premenopausal women, 220, 221symptomatic side effects, 222tamoxifen, 223, 224TransATAC trial, 223

Adjuvant Tamoxifen: Longer Against Shorter (ATLAS), 165

Adjuvant tamoxifen therapyclinical trials, 164long term (see Long-term adjuvant

tamoxifen therapy)treatment, MBC, 164

Adjuvant Tamoxifen Treatment offers more (aTTom), 165

Adjuvant therapy, 173AdoMet binding, 80Adrenalectomy, 167Adult αERKO mice, 23AI therapy, 158AKT-induced estrogen-regulated genes, 62AKT/mTOR pathway, 140Alkylphenols, 351American College of Surgeons Oncology

Group (ACOSOG), 226

American Society of Clinical Oncology (ASCO), 223

Amino acids 263-302, 51Anastrozole-resistant cells, 140Androgen action, 172Androgen insensitivity syndrome (AIS), 37Androgen receptor (AR), 12Antiandrogenic treatment, prostate cancer, 8Antibodies, 7, 8Anti-estrogen action, 171Anti-estrogenic isomer, 153Anti-estrogenic properties, 151Anti-estrogenic region, 160Antiestrogens (AEs)

antagonist-specific continuum, 243binding sites, 10, 11cofactor recruitment and gene

transcription, 251–252E2, estriol and estrone, 242epilogue, 242, 244–247, 254ERα post-translational

modifications, 252, 253ERβ, 243ERs

architecture and sequence homology, 243, 244

disordered ER NH2-terminus, 248domain structure and response element

recognition, 247–248helix 12 conformational switch, 244–246modulators and selective ER

downregulators, 248, 249mutations, 253, 254

molecular rationale of, 250–251pathological conditions, 242

Index

408

Antiestrogens (AEs) (cont.)SERM, 9, 10structural studies, 243tamoxifen, 131X-ray crystallography studies, 243

Antifertility, 153Antithrombin III, 163Anti-uterotrophic action, 191Armamentarium, 217, 218Aromatase inhibitors (AIs), 140, 216, 217, 221Arylsulfatase, 356Arzoxifene, 195Atomic Bomb Project, 3aTTom trial, 224

BBazedoxifene, 194, 197, 198Beta-glucuronidase, 356Bisphenol A (BPA), 143

activities, 361apoptosis by cisplatin, 360and BPS

monomers, 366substitute, 366–367

breast tumorigenesis, 372chemical industry, 368CLARITY-BPA, 369–371doxorubicin, cisplatin and vinblastine, 359endocrine disruptive activity, 355endocrine society, 368environmental advocacy groups, 367–368ERα and ERβ, 362ERR, 364–365ERRγ, 372GPER, 363–364, 372health organizations and regulatory

agencies, 369human exposure, 355–356human health, 373hyperprolactinemia, 370intracellular ER𝛼/ER𝛽, 361–363in vitro and in vivo studies

genomic and non-genomic effects, 357–358

induction of chemoresistance, 358, 359pathophysiological and oncogenic

actions, 357perinatal actions, 359–361

legislative decisions, 371–372mammary gland, 373mechanisms, 362membrane ERs, 363

molecular mechanisms, 365–366mutagenic/genotoxic chemicals, 372non-human models, 372pathophysiology, 367production and environmental

sources, 354publications, 367steroidal/non-steroidal receptors, 361synthesis, 354T47D and MDA-MB-468, 365

Bone mineral density (BMD), 30Bone/skeletal system, 29, 30BPA diglycidylether (BADGE), 354, 371BPA diglycidyl methacrylate

(bis-GMA), 354, 355Brain, 30, 31Breast cancer

antiestrogenicity, 254biology and therapy, 310characterization, 331chemoprevention, tamoxifen, 166, 167disease recurrence, 325EGFR, 319ERα, 249ERα-positive, 310, 314, 323and ER status, 27, 28and estrogen signaling

EIA, 8ER assay kits, 9ERICA, 9ER-positive and ER-negative, 8, 9mastectomy, 8menstrual cycle, 8

human mammary, 319in cellula and in vivo human, 251initiation and progression, 309mammary epithelial, 320MCF-7, 253metastasis, 324metastatic, 249, 254miR-92, 316miRNAs in (see MicroRNAs (miRNAs))pro-differentiation factor, 324prognosis, 310risks, 344sensitization, 253therapy and prevention, 153

Breast Cancer Symposium, 174, 177Breast carcinogenesis, 364Breast-conserving surgery (BCS), 226Breast International Group 1-98 Trial

(BIG 1-98), 224British Special Air Service (SAS), 176

Index

409

CcAMP-response element binding protein

(CREB), 55Cancer stem cells (CSC), 134Cardiovascular disease (CVD), 32, 33Carryover effect, 164CARM1, 74, 78–81, 83–85CDK4/6 cell cycle signaling, 381, 383, 384Chemoprevention, breast cancer, 166, 167ChIA-PET, 59, 60ChIP-on-chip, 57, 62ChiP-Seq analysis, 22Chloroindazole (CLI), 23Chromatin immunoprecipitation (ChIP)

assays, 56, 107, 113Chromosome conformation capture (3C), 59, 61Chromosome looping, 59, 60Chronic obstructive pulmonary disease

(COPD), 33Cistrome, 96, 98, 105, 112, 113

ERαgenome-wide analyses, 56, 57growth factor signaling regulation, 62, 63

Cixutumumab, 389Classical and nonclassical ERα binding

modes, 54, 55Clinical Treatment Score post-5 years

(CTS5), 223Clomiphene, 152, 153, 155, 170CLTC, 139c-Myc enhancer, 55Co-activator-associated arginine

methyltransferase 1 (CARM1), 391, 397

Coactivatorscryo-EM technology, 85diverse functions, 72DNA-binding domain, 72LBD, 72structural studies (see Structural studies,

coactivators)transcription, 71

Cohesin, 60Comparison of Raloxifene and Lasofoxifene

(CORAL), 197Condensin, 60Conjugated equine estrogen

(CEE), 194, 197, 198Coumestans, 346CREB-binding protein (CBP), 391CREB-binding protein (CBP)/p300

acyl-CoAs, 76binding specificity, 78

bromodomain, 77catalytic core, 74CH2 region, 77C-terminus, 78E1A-associated proteins, 74HAT activity, 76KATs, 76KDa proteins, 74NCBD domain, 78PHD finger, 77protein-protein interaction, 77RING domains, 77TAZ1 and TAZ2, 77, 78X-ray structure, HAT domain, 76, 77

Cre-driven recombination, 20Cre-loxP system, 18Crocodile model, 159, 162Crosstalk

DDR machinery and hormone signaling pathways, 283

ERand ERK1/2 pathway, 273and GFR signaling, 272and receptor tyrosine and cellular

kinases, 268–277and SRC/FAK signaling, 274

tyrosine and intracellular kinases, 269Cryo-EM, 81, 82, 85Cryptorchidism, 349Cutting-edge technology, 172Cyclin-dependent kinases (CDKs), 381Cytoplasmic and nuclear signaling

pathways, 97

DDalotuzumab, 389DALRD3, 135Diarylpropionitrile (DPN), 318Dicer protein expression, 141Dichloro-diphenyl-trichloroethane

(DDT), 143, 353Diethylstilbestrol (DES), 2, 34, 38, 349, 354,

358, 360Disrupted ER signaling, 36–38Distant metastasis-free survival (DMFS), 271,

284DMBA model, 172DNA-binding domain (DBD), 17, 22, 50, 72,

244, 245, 247, 248DNA damage response

and repair (DDR), 283Drosha microprocessor complex, 130

Index

410

Drug monitor, ICI46,474 Lois Trench, 170, 171Ductal carcinoma in situ (DCIS), 218–220

EEarly Breast Cancer Trials Collaborative

Group (EBCTCG), 165, 174Eastern Cooperative Oncology Group

(ECOG), 171Elusive mechanism, estrogen, 2Elwood Jensen, 3, 4

ER (see Estrogen receptor (ER))Endocrine-disrupting chemicals (EDCs)

BPA (see Bisphenol A (BPA))breast cancer, 344–346canonical and non-canonical pathways, 344classes of phytoestrogens, 347definition, 343estradiol and diethylstilbestrol, 350man-made chemicals, 349natural xenoestrogens (see Natural

xenoestrogens)synthetic xenoestrogens (see Synthetic

xenoestrogens)xenoestrogens, 344

Endocrine disruptors and miRNAs, 143Endocrine resistance

anti-estrogen therapies, 380AP-1 binding, 267breast cancer, 266CDK4/6

cell cycle signaling, 381, 383, 384inhibitor drugs, 382RB and cell cycle pathway, 276–277

DNA damage response pathway, 283EGFR family members, 397endocrine therapy, 267epigenetic alterations, 281–282ER activity, 278–279

agents, 277and receptor tyrosine and cellular

kinases, 268–277ESR1 amplification, 280, 281genomic aberrations, 277pioneer factors, 280transcriptional coregulators, 279–280transcriptional reprogramming, 268

ER cofactors, 390–397ER/HER2 signaling pathway, 394FGFR signaling, 271–272GFR signaling, 268growth factor signaling pathways, 380, 381HER family, 268–270

IGF-1/IGF-1R pathway, 388–390IGF pathway, 270–271immunotherapies, 397inter- and intra-tumoral heterogeneity, 285intracellular signaling cascades

and disease progression, 272p38, JNK/AP-1 and NFκB signaling,

275–276PI3K/AKT/mTOR, 272–273RAS/RAF/MEK/ERK, 273–274SRC/FAK signaling, 274–275

intra-tumoral heterogeneity, 268, 285MED1, 392–394, 396, 397and miRNAs

anastrozole-resistant cells, 140aromatase inhibitors, 140in breast cancer, 138CLTC, 139dysregulation, miRNAs, 136estrogen-dependent regulation, 139estrogen-induced expression, 138estrogen stimulation, 138HOXB7, 139, 140lentivirus-based approach, 139letrozole-resistant cells, 140LTED cells, 138LY2 cells, 136MCF7, 136microarrays, 137miR-124, 138miR-221/222, 136miR-378a-3p, 138, 139miR-519a, 136miR-574-3p, 139miRhub, 137miRs, 138and mRNAs, 137and mTOR signaling pathways, 137POMP, 140, 141proteasome inhibition, 140by qRT-PCR, 138tamoxifen therapy, 136TamR cells, 136, 138ZNF217 3’-UTR reporter assay, 137

molecular mechanisms, 267, 398normal mammary gland, 266PDX models, 285PI3K/AKT/mTOR pathway, 384, 385, 387,

388PI3K/mTOR/AKT inhibitors, 386–387primary modalities, 267pRNA-HER2apt-siMED1 nanoparticles, 395p160/SRC1/2/3, 391–392

Index

411

quality of life, 285RNA nanotechnology, 380SERDs, 267structural and functional organization, 266tumor microenvironment and immune

response, 283–285Endocrine therapy (ET)

adjuvant (see Adjuvant endocrine therapy)armamentarium, 217, 218Beatson’s historical observation, 216breast cancer patients, 216CDK4/6 inhibitors, 216chemoprevention strategies, 218, 219clinical practice, 216expression, 216in situ tumors, 219, 220inter and intra tumoral genomic

heterogeneity, 233MBC (see Metastatic breast cancer

(MBC))molecular biology, 216mTOR inhibitors, 216neoadjuvant (see Neoadjuvant endocrine

therapy (NET))SERD therapy, 232

Endocrine-resistant cell line, 133Endometriosis, 23Endothelial cells (ECs), 20, 32Endothelial NOS (eNOS), 33Endoxifen, 158Enhancer

active ERα, 100active estrogen-regulated, 111, 112assembly, 105enhancer-promoter looping, 105, 107features, 98formation and activity, 102landscapes and transcriptional outcomes, 113ligand-dependent ERα, 104target genes of ERα, 112, 113transcription, 98, 99, 110, 111

Enhancer RNAs (eRNAs), 61, 62, 111Enterohepatic recirculation, 157Environmental Protection Agency (EPA), 369Enzyme immunoassay (EIA), 8Epidermal growth factor (EGF), 63, 270Epidermal growth factor receptor (EGFR),

318, 319, 324, 327Epigenome, 96, 111Epithelial-mesenchymal transition (EMT),

132–134, 282, 310, 324ERα

binding modes, 54–55cistrome, 62–63

cofactors, dynamic and cyclic recruitment, 55, 56

domain structure, 50, 51gene transcription, 55, 56PMT (see Post-translational modifications

(PTMs))ERα-mediated gene transcription

eRNAs, 61, 62ERα cofactors in, 55, 56molecular model, 58

ER assay kits, 9breast tumors, 172

ER associated protein, (ERAP), 7ER domain structure and receptor

dimerization, 6αERKO, 18, 21–24, 26, 27, 29, 31, 33, 35–37βERKO, 18, 23, 26, 27, 31, 36Esr1KO mice, 28Estrogen

elusive mechanism, 2metabolic regulation, 35–36signaling and breast cancer, 8, 9

Estrogen receptor (ER), 216, 217adrenalectomy, 167anticancer agent, 174antiestrogens (see Antiestrogens (AEs))binding domain, 153CYP2D6, 158discovery, 5, 49domain structure, 6endoxifen, 158ERα (see ERα)hormone, 54-hydroxytamoxifen, 158in MBA, 167measurement techniques, 172mechanisms, 154miRNAs (see MicroRNAs (miRNAs))molecular modulation, prolactin synthesis,

159, 160, 162nongenomic activity, 164physiological and pathological roles (see

Physiological and pathological function, ER)

production, antibodies, 7, 8protein and cloning, SRC-1, 7and RNA synthesis, 68S, 173SERMs, 155structural validation, 11, 12tamoxifen (see Tamoxifen)

Estrogen receptor β (ERβ)anti-proliferative effects, 321–322anti-tumor actions, 310

Index

412

Estrogen receptor β (ERβ) (cont.)breast tumors, 310, 325–326cell proliferation, 322–323

and survival, 320–323clinical outcome, 327–331clinicopathological characteristics, 326–327and ERα, 310genomic

and epigenetic changes, 332and functional structure, 311

immune system and fibroblasts, 332inadequate expression, 331invasion and migration, 323–325LBD structure, 11ligand-independent activation, 314–315mechanism, 310–315normal mammary gland

and cell proliferation, 318–319and epithelial differentiation, 319sources of reproductive hormones, 318transplantation experiments, 318

nuclear receptor, 309prognostic markers and clinical

outcome, 328–330pro-tumorigenic function, 310regulation, 142, 143

anti-tumorigenic role, 315degradation, 317mRNA level, 315–316post-translational level, 316

splice variants, 319–320transcription factors, 314

Estrogen receptor gene (ESR1), 37Estrogen-regulated transcriptome

active ERα enhancers, 100active estrogen-regulated enhancers, 111, 112and cAMP signaling, 114challenges and opportunities, in genomic

analyses, 105coregulators, ER

functions, 102and noncoding RNAs, 102proteins and complexes, 100

ERα binding sitescistromes and transcriptional

enhancers, 98direct and indirect, 99, 100

extracellular stimuli, 113gain-of-function ERα mutations, 116, 117genetic mutations, 117genomic amplification, regulatory

elements, 116genomic approaches, 107

genomic ChIP assays, 107on genomic scale, 105GRO-seq and derivatives, 109–111and growth factor signaling, 114, 115landscapes and transcriptional outcomes, 113luminal/ER-positive breast cancers, 115methodological challenges, 118microarray-based genomic

technologies, 105microarrays and RNA-seq, 107–108Pol II recruitment and promoter-proximal

pausing, 104and proinflammatory signaling, 115protein-coding mRNA genes, 102RNA Pol II transcriptome, 111target genes, ERα enhancers, 112, 113transcriptional responses, 103

Estrogen regulatory element (EREs), 50Estrogen-related receptors

(ERRs), 142, 143, 361Estrogen-responsive elements (EREs), 17, 54,

55, 267, 312–314Estrogen signaling, 318, 320, 325Estrophilin, 5Ethamoxytriphetol (MER25)

anti-estrogen, 151anti-estrogenic properties, 151anti-estrogenic side chain, 153antifertility agent, 152structure, 151

European Food Safety Authority (EFSA), 371

FFermi lab, 3Fetal/neonatal mammary glands, 26Flavonoids, 346Focal adhesion kinase (FAK), 269, 274–275Follicle-stimulating hormone (FSH), 38, 163Forkhead (FKH) motif binding sites, 63FOXA1, 58, 59Fulvestrant, 131, 163, 218, 230–232

GGail model, 219Ganitumab, 389Gastrointestinal (GI) tract, 34, 35General transcription factors (GTFs), 392Genetic aberrations

GFR signaling, 278–279NCOA2/NCOA3, 279

Genome-wide analyses, 56, 57

Index

413

Genome-wide studiesERα

chromosome looping, 59, 60eRNAs, 61, 62pioneer factors, 57–59

Genomic and nongenomic signal transduction pathways, 164

Global run-on sequencing (GRO-seq), 61, 109enhancer transcription and eRNAs, 111estrogen-dependent transcriptional

responses, 109–110histone marks, from ChIP-seq, 113lncRNA gene, 110

Glucocorticoid receptor, 5Good laboratory practice (GLP), 370G-protein-coupled estrogen receptor (GPER),

28, 344, 348, 361–365, 372Growth factor receptors (GFRs)

cell surface integrin, 274cellular signaling, 277downstream intracellular kinase

signaling, 268EGFR, 269, 271, 272HER2, 269hyperactivation, 269IGF1R and IGF1, 269signaling molecules, 267

Growth signaling pathways, 380–390

HHealth hazard, 368, 369Heat shock proteins (HSPs), 316Helix 10, 51[3H] estradiol, 159[3H] labeled 4-hydroxytamoxifen, 159High affinity binding (HAB), 160High density lipoprotein-(HDL) cholesterol, 32Histone acetyltransferases (HAT), 251Histone deacetylases (HDACs), 135, 251Histone methyltransferases (HMTs), 251Homologous recombination, 20Hormonal activator E2, 17Hormone replacement therapy

(HRT), 194, 345, 350Hormones, 1–6, 8HOXB7, 139, 140Huggins model, 17227-Hydroxycholesterol (27HC), 334-Hydroxytamoxifen (4-OHT), 190, 245, 246,

249–251, 253, 254Hyperinsulinemia, 389, 390Hypothalamic-pituitary axis, 24Hypothalamic-pituitary-gonadal

(HPG) axis, 25, 26

IICI46,474, 155, 167, 169–171, 173IGF-1/IGF-1R pathway, 388–390Immune system, 34Immunocytochemical assay, 9Immunohistochemistry (IHC), 28, 266Impaired glucose tolerance (IGT), 35Imperial Chemical Industry (ICI), 153, 155,

167–171, 174, 176, 180Insulin-like growth factor receptor

(IGF1R), 269–271, 273Insulin resistance, 35International Breast Cancer Intervention Study

(IBIS), 166Invasive ductal carcinoma (IDC), 271, 280Invasive lobular carcinoma (ILC), 280In vitro cell reporter assay, 22Isoflavones, 346The Italian Study, 166

JJMJD2B, 135

KKeoxifene, 155

LLasofoxifene, 194, 196, 197, 201Leiomyosarcoma, 22Lentivirus-based approach, 139Letrozole-resistant cells, 140Ligand-binding domain (LBD), 17, 51, 72,

243–246, 248, 250, 281Ligand-dependent transcription factors, 72Lignans, 346Liver X receptors (LXR), 33Lobular carcinoma in situ (LCIS), 218, 219Long noncoding RNAs (lncRNAs), 110Long-term adjuvant tamoxifen therapy

ATLAS, 165aTTom, 165clinical care, 165EBCTCG, 165mindless exercise, 165NSABP node-negative trial B14, 165primary breast cancer, 165the carryover effect, 164

Low density lipoprotein (LDL)-cholesterol, 32

Lung, 33, 34Luteinizing hormone (LH), 28, 38, 163LY156758 mesylate, 206

Index

414

MMale reproductive tract, 28, 29Mammary gland, 26, 27Mastectomy, 8Matrix metalloproteinase-2 (MMP-2), 365Matterhorn experience, 2MCF-7 breast cancer cells, 169MCF-7AKT, 62Mechanism of action, 372Mediator subunit 1 (MED1), 392–394, 396, 397Medroxyprogesterone acetate (MPA), 197, 198Megestrol acetate, 232Membrane estrogen receptors

(mERs), 347, 362, 363Menstrual cycle, 8Menstrual/estrous cycle, 20Merrell’s second anti-estrogen MRL41, 153Metabolic syndrome, 35Metastatic breast cancer

(MBC), 189, 190, 198, 204abemaciclib, 229burden and mutational plasticity, 164cancer therapy, 158CDK4/6 inhibitors, 229endocrine agents, 229endocrine-naïve patients, 230FALCON trial, 230first-line phase III clinical trials, 229ICI46,474, 170palbociclib, 229ribociclib, 230second-line ET, 230–232statistical and clinical benefits, 230tamoxifen resistance, 163treatment, 154, 155, 164, 168, 174

Methylation, 53MicroRNAs (miRNAs)

biogenesis, 130, 131dysregulation, 130endocrine disruptors, 143and endocrine resistance (see Endocrine

resistance)ERα levels, 130ERα regulation

antiestrogen therapies, 131CSC, 134EMT, 132–134ligand specificity, 131MCF7 cells, 132miR-21, 131, 132miR-221/222, 131, 132miRNome, 132proliferation, 135

ERβ regulation, 142, 143ERRs, 142, 143gene regulation, 130noncoding RNAs, 130ORF, 130procession machinery, 141, 142translation/degradation, 130UTR, 130

Mindless exercise, 165miR-200 family, 132miR-21, 130MiR-221/miR-222, 136MiR-574-3p, 139miRhub, 137miRNome, 132Mismatch repair pathway (MMR), 283Mitogen activated protein kinase (MAPK),

268, 270, 271, 273, 274, 284Molecular mechanisms, ER mediated

signaling, 16, 17Molecular pharmacology, 158, 159Monoclonal antibodies, 7, 159Mouse models, 18, 19mRNAs, 130, 131, 134, 137mTOR signaling pathways, 137Multiple Outcome of Raloxifene Evaluation

(MORE) trial, 206Mycoestrogens, 348Myometrium, 20

NNafoxidine, 153, 154National Center for Toxicological Research

(NCTR), 369National Institute of Environmental Health

Sciences (NIEHS), 369National Surgical Breast and Bowel Project

(NSABP), 171National Toxicology Program (NTP), 369, 371Natural xenoestrogens

mycoestrogens, 348natural and synthetic compounds, 346phytoestrogens, 346–348

Neoadjuvant endocrine therapy (NET), 226, 228early-stage luminal tumors, 226endocrine agents, 227postmenopausal women, 226

Nitrogen oxide synthase (NOS), 33Noncoding RNAs, 130Non-genomic ERα signaling, 19Non-monotonic dose-response (NMDR), 357Nonreproductive tissue, 4

Index

415

Nonsteroidal anti-estrogens, 151–154, 156, 167, 168, 172

Non-steroidal aromatase inhibitor (NSAI), 383The NSABP P-1 Study, 166Nuclear localization sequence (NLS), 51Nuclear receptor coactivators

(NCOAs), 279, 281Nuclear receptor family, 4, 5Nuclear receptors, 17, 18

OOctylphenols, 3514OHT ligand-binding site, 11Oophorectomy, 173Open reading frame (ORF), 130, 131Oral contraceptives, 345, 350Order of the British Empire (OBE), 176, 180Ospemifene, 198Osteoporosis Prevention and Lipid Lowering

(OPAL), 197Ovarian function suppression

(OFS), 216, 231, 232Ovarian suppression, 221Ovary, 23–25Ovulations, 153, 155, 163, 168

PPalbociclib, 229, 231, 381, 383, 384Palmitoylation sites, 22Patient-derived xenograft (PDX), 272Peroxidase-antiperoxidase (PAP) reagent, 9Peroxisome proliferator activated receptor

(PPAR), 344, 365PH domain, 80, 81Phosphatase 2A (PP2), 32Phosphatidylinositol 3-kinase

(PI3K), 268, 270–273Phosphorylation, 51, 52Physiological and pathological function, ER

behavior, 31bone/skeletal system, 29, 30brain, 30, 31CVD, 32, 33disrupted ER signaling, 36–38endometriosis, 23ER status and breast cancer, 27, 28G axis, 25GI tract, 34, 35HPG axis, 26immune system, 34lung, 33, 34male reproductive tract, 28, 29

mammary gland, 26, 27molecular mechanisms, 16, 17mouse models, 18, 19ovary, 23–25radiolabeled estradiol, 16uptake and tissue retention, 15uterine cancer, 22, 23uterus, 20–22

Phytoestrogens, 346–348and breast cancer, 347intracellular ERs, 347in vitro and in vivo studies, 348plant-derived compounds, 346sub-classification, 346

PI3K/AKT/mTOR pathway, 384, 385, 387, 388

Pioneer factors, 57–59Polychlorinated biphenyls (PCBs), 352Polyclonal antibodies, 7Polycyclic aromatic hydrocarbons

(PAH), 352–353Post-menopausal Evaluation and Risk

Reduction with lasofoxifene (PEARL), 197

Post-translational modifications (PTMs), 243, 252, 253

acetylation, 53cistrome, 56, 57ERα

binding modes, 54–55chromosome looping, 59, 60eRNAs, 61, 62pioneer factors, 57–59

methylation, 53phosphorylation, 51, 52ubiquitination, 52, 53

pRNA–HER2apt–siMED1 nanoparticles, 395–397

Progesterone receptor (PR), 5, 27Progression free survival (PFS), 267, 381, 383Prolactin synthesis, tamoxifen, 159–162Proliferation, 135Prostate cancer, 2Proteasome inhibition, 140Proteasome maturation protein

(POMP), 140, 141Protein arginine methyltransferase (PRMT)

family, 79, 80Protein arginine N-methyltransferase 1

(PRMT1), 391Protein kinase A (PKA), 62Protein-protein inter, 74, 77, 78, 81, 83Provocative model, 10Pulmonary, 33

Index

416

QQ mutation, 37qRT-PCR, 139Queen’s Award for Industry, 174, 175

RRadiolabeled estradiol, 16Raloxifene, 155, 160, 193–195, 197, 199, 201,

204, 206, 243, 245, 248–253Receptor tyrosine kinases (RTKs), 268–270,

272, 273Reproduction, 28, 30, 34Reproductive tissues, 28Retinoic acid receptor, 5R394H mutation, 38Ribociclib, 229, 232, 381, 383, 384RNA-induced silencing complex (RISC), 131RNA nanotechnology, 380, 391, 393, 394RNA Pol II transcriptome, 111RNA synthesis, 6Rossmann fold structure, 80The Royal Marsden Study, 166

SSarcoma, 22Selective androgen receptor modulators

(SARMs), 201Selective estrogen receptor downregulators

(SERDs), 242, 249, 252, 253, 267, 271, 281

Selective estrogen receptor modulators (SERMs), 9, 10, 155, 156, 158, 160, 162, 167, 168, 194–196, 201, 203–205, 217, 243, 248–250, 252, 253, 267, 277, 279, 281, 283

AEBP, 191athymic rodent model, 191available and Ideal, 195bisphenol, 191bitransplantation study, 1924-chlorotamoxifen, 190clinical trials, 190development, 194–199endometrial carcinomas, 193experimental compounds, 201expression, 2004-hydroxytamoxifen, 190keoxifene, 193–194laboratory/literature clues, 196MBC, 189mechanism, 199–201

metabolite E, 190pharmacology, 189photographs, 203steroid therapies, 201tamoxifen, 190–193UWCCC, 201, 202, 204–206

Selective glucocorticoid receptor modulators (SGRMs), 201

Selective mineralocorticoid receptor modulators (SMRMs), 201

Selective peroxisome proliferator-activated receptor modulators (SPPARMs), 201

Selective progesterone receptor modulators (SPRMs), 201

Selective thyroid receptor modulators (STRMs), 201

Sex hormone, 163Small molecule inhibitors, 389, 391Sprague Dawley (SD) rats, 355Steroid hormone estrogen, 49Steroid receptor coactivators (SRCs), 7,

72–74, 274, 275, 391, 392Stilbens, 346Structural studies, coactivators

complexesCARM1, 83Cryo-EM, 81ERα, SRC-3 and p300 proteins, 82, 83full-length coactivators, 81nuclear receptor-targeted

transcription, 81individual

CARM1, 78, 80, 81CBP/p300, 74, 76–78SRCs, 72–74

SUMOylation, 253Suppression of Ovarian Function Trial

(SOFT), 221Synthetic xenoestrogens

cosmetics, 350–351detergents, 351–352food additives, 351herbicides, 353PAH, 352–353pesticides, 353pharmaceuticals, 349–350preservatives, 351–352

TTamoxifen, 10, 136, 217, 242, 243, 248–253

adjuvant tamoxifen therapy, 164, 165anticancer actions, 172

Index

417

anti-estrogen, 163anti-estrogenic isomer, 153anti-estrogenic properties, 151antifertility, 153, 155antithrombin III, 163athymic rats, 163chemoprevention, breast

cancer, 155, 166, 167clinical applications, 163clinical endocrinology, 162, 163clinical pharmacology, 155, 162, 163clinical strategy, 155clinical testing, 155clinical trials, 163clomiphene, 152, 153, 155endoxifen, 158FSH, 163fulvestrant, 163genomic and nongenomic signal

transduction pathways, 164hydroxylated metabolites, 157ICI, 155isomers, 153keoxifene, 155LH, 163MBC (see Metastatic breast cancer (MBC))mechanisms, 162MER25 (see Ethamoxytriphetol (MER25))metabolic activation, 157, 158metabolism, 156–158, 162molecular mechanisms, 163molecular pharmacology, 158, 159nafoxidine, 153, 154ovulations, 155, 163pharmacological properties, cis and trans

isomers, 155prolactin synthesis, 159–162raloxifene, 155resistance, 163SERMs, 155side chain, 157synthetic estrogens, 155triparanol, 153

Tamoxifen and Exemestane Trial (TEXT), 221Tamoxifen-resistant (TamR), 136, 268, 274, 282Target gene DNA motif, 17Thyroid receptor (TR), 12Toremifene, 189, 190, 198Transcriptional reprogramming

in endocrine resistance, 267ER activity, 269, 277, 280, 284

Transcription factor and cofactors, 1, 7Transcriptome, 96

estrogen signaling, 103 (see also Estrogen- regulated transcriptome)

Transforming growth factor β (TGF-β), 62Trichostatin A (TSA), 135Triparanol, 152, 153Triphenylethylene, 151, 153, 155, 159, 167, 168Tritiated estradiol, 4Tritiation apparatus, 3Tritiumator, 3Tumor-associated macrophage (TAM), 284Tumor microenvironment, 269, 276, 283–285Tyrosine kinase inhibitor (TKI), 389

UUbiquitination, 52, 53, 253University of Wisconsin Clinical Cancer

Center (UWCCC), 174, 202, 204Uterine cancer, 22, 23Uterus, 20–22

VVascular smooth muscle cells (VSMCs), 32

W3WJ pRNA–HER2apt–siMED1

nanoparticles, 396Women’s health

breast cancer, 201WHI, 197

Worcester Foundation for Experimental Biology (WFEB), 169–173

WT mice, 21

XXenoestrogens

estrogenic effects of, 370estrogenicity of, 357natural (see Natural xenoestrogens)synthetic (see Synthetic xenoestrogens)types of, 344

ZZearalenones, 348ZNF217 3’-UTR reporter assay, 137

Index