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TitleAdvances in Rapid Sex-Steroid Action - G. Castoria, et. al., (Springer, 2012) WW
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Table of Contents
                            001Download PDF (1.6 MB)front-matter
	Advances in Rapid
Sex-Steroid Action
		Preface
		Contents
		Contributors
002Download PDF (1.4 MB)front-matter
	Part I
Breast Cancer
003Download PDF (1.8 MB)fulltext
	2 ProgesteroneProgesterone Signaling to ChromatinChromatin in Breast Cancer Cells. Two Initial Cycles of Remodeling
		Abstract
		1…Introduction
		2…NucleosomeNucleosome Organization is Required for Efficient PR Binding and Gene Regulation
		3…Preparing the Chromatin for Gene Regulation
		4…BRCA1BRCA1 as a Physiological Brake for Hormone Action
		5…Conclusions
		Acknowledgments
		References
004Download PDF (1.8 MB)fulltext
	3 Cooperative Interactions Between c-Src, Estrogen Receptors and Receptor Tyrosine Kinases in Breast Cancer
		Abstract
		1…Introduction
		2…Canonical vs Rapid Signalingsignaling of Estrogen and the ERs
		3…Rapid Estrogen Signalingsignaling Involving ER, c-Srcc-Src and HER Family Members
			3.1 EstrogenEstrogen-Dependent c-Srcc-Src-ER Interactions: Complexes, Physiological Role, Mechanism of Action, and Regulation
			3.2 EstrogenEstrogen-Dependent HER Family and ER Interactions
			3.3 EstrogenEstrogen-Independent Interactions Between ER, c-Srcc-Src, and HER Family Members
			3.4 EstrogenEstrogen Receptor-Independent Actions of c-Srcc-Src and HER Family Members in Breast Cancerbreast cancer
		4…AR in Breast Cancerbreast cancer and Possible Interactions With ER, c-Srcc-Src, and HER Family Members
		5…ProgesteroneProgesterone Receptor Interactions With ER, c-Srcc-Src and HER Family Members
		6…Cancers Other Than Breast Cancerbreast cancer Whose Etiology is Influenced by the Estrogen Receptorestrogen receptor, c-Srcc-Src, and HER Family Members
		7…Role of c-Src/HER Family in Resistance to Hormone, Cytotoxic, or Targeted Therapies in Breast Cancerbreast cancer
			7.1 c-Srcc-Src as a Resistance Factor in Hormone, Cytotoxic, and Targeted Therapies in Breast Cancerbreast cancer
			7.2 c-Srcc-Src as a Resistance Factor to Hormonal Therapy in Breast Cancerbreast cancer
			7.3 c-Src and EGFR as Resistance Factors to Cytotoxic Therapies in Breast Cancerbreast cancer
			7.4 c-Srcc-Src and EGFR as Resistance Factors to Inhibitors of EGFR Family Members
		8…c-Srcc-Src/HER Family Targeted Therapies in Single Agent or Combinatorial Studies
			8.1 c-Srcc-Src Targeted Therapies
			8.2 EGFR and HER2 Inhibitors
		Acknowledgments
		References
005Download PDF (1.7 MB)fulltext
	4 Cross Talk Between ER alpha and Src Signaling and Its Relevance to ER Status and Hormone Responsiveness
		Abstract
		1…Estrogen Receptor in Breast Cancer
		2…Mechanisms Underlying ER Loss in Breast Cancer
			2.1 ER Gene Changes
			2.2 ER Promoter Hypermethylation
			2.3 ER mRNA Expression in Breast Cancerbreast cancers
			2.4 MAPK Activated Loss of ER Expression
		3…EGFR Family and Src Kinase Activation in Breast Cancer
		4…ER Cross-Talk with Signaling Transduction Pathways
		5…ER Phosphorylation by Src
		6…The Link Between Steroid Hormone Receptor Activation and Receptor Degradation
		7…Src Promotes Ligand Activated ER Degradation and ER Target Gene Transcription
		8…Implications for the Definition of an ‘‘Estrogen Responsive’’ Tissue
		References
006Download PDF (1.9 MB)fulltext
	5 Post-translational Modifications of ER Alpha in Rapid Estrogen’s Action
		Abstract
		1…Introduction
		2…PTMs Involved in ER Non-genomic Signaling
			2.1 Palmitoylation
			2.2 Phosphorylation on Tyrosine (Y)
			2.3 Arginine Methylation
		3…Conclusions
		Acknowledgments
		References
007Download PDF (1.7 MB)fulltext
	6 Sex-Steroid Rapid Action and Its Role in Invasiveness and Metastasis of Breast Cancer
		Abstract
		1…Introduction
		2…Non-genomic Actions by Steroid Hormones
			2.1 Rapid Action of Steroids Involving Classical Intracellular Steroid Receptors
			2.2 Rapid Action of Steroids Involving Non-classical 	Membrane-Bound Steroid Receptors
			2.3 Rapid Action of Membrane Steroid Receptors 	Involving G Protein-Coupled Receptors (GPCR)
			2.4 Rapid Action of Membrane Steroid Receptors via 	Trans-Activation of Growth Factor Receptors
			2.5 Rapid Non-transcriptional Action of Membrane 	Steroid Receptors
		3…Sex Steroids and Actin Cytoskeleton Remodeling
			3.1 Sex Steroids and Ezrin/Radixin/Moesin
			3.2 Sex Steroids and Focal Adhesion Kinase
		4…Sex Steroids and Tyrosine Kinase Receptor
		5…Sex Steroids and Other Metastasis-Associated Molecules
			5.1 Chemokines and Their Receptors
			5.2 Integrins
			5.3 Role of p52Shc in Steroid-Regulated Cell Proliferation and Migration
		6…Conclusions
		References
008Download PDF (1.6 MB)fulltext
	7 Unraveling the Role of GPERGper in Breast Cancer
		Abstract
		1…Introduction
		2…GPERGPER SignalingSignaling in Breast CancerBreast Cancer
		3…Binding Specificity and Biological Characterization of GPERGPER Ligands
		4…Implication of GPERGPER in the Resistance to Antiestrogen Therapy
		5…GPERGPER as a Biological Marker in Breast Carcinomas
		6…Conclusions
		Acknowledgments
		References
009Download PDF (1.7 MB)fulltext
	8 Nongenomic Actions of Estrogens and Xenoestrogens Affecting Endocrine Cancer Cells
		Abstract
		1…Introduction
		2…Receptors and the Signalingsignaling Responses and Functions Associated with Them
		3…Time-Oscillating Responses
		4…Hormesis-Nonmonotonic Responses
		5…Estrogenic Ligands: Physiologic and Non-physiologic
		6…Responses to Ligand Mixturesligand mixtures
		7…Developmental and Immune Systemimmune system Effects, Affecting Cancer
		8…Summary
		Acknowledgments
		References
010Download PDF (1.7 MB)fulltext
	1 Non-genomic Action of Steroid Hormones: More Questions than Answers
		Abstract
		1…Introduction
		2…Phenotype Dependence on Hormone Concentration: An Isolated Case or a General Rule?
		3…Migration and Proliferation Dichotomy Regulated by Rapid Hormonal Actions: A Step Towards Hormone Resistance?
		4…Non-Reproductive Cells Express Very Low Amounts of Steroid Receptors: A Model of ‘Pure’ Non-Genomic Receptor Action?
		5…Growth Factor Signaling Depends on Extra-Nuclear Steroid Receptors: Are Other Partners Implicated?
		6…Hetero-Association Between Steroid Receptors: A Tool to Enhance Hormone Signaling?
		7…The Proliferative Role of Steroid Receptor Nuclear Export: A Paradox of Classic Receptor Transcriptional Action?
		8…Receptor/Protein Associations: A Promising Target for Cancer Therapy?
		Acknowledgements
		References
011Download PDF (1.4 MB)front-matter
	Part II
Prostate Cancer
012Download PDF (1.8 MB)fulltext
	9 Differential Functions of Stromal and Epithelial Androgen Receptor in Prostate Cancer Before and After Castration Resistant Stage
		Abstract
		1…Introduction
		2…Epithelial AR Role in PCa
			2.1 Epithelial AR Role in In Vitro PCa Cell Line Studies (Growth vs. Invasion)
			2.2 Epithelial AR Role in PCa Mouse Model Studies (Initiation vs. Metastasis)
			2.3 AR Role in CK5-Positive vs. CK8-Positive PCa Cells
		3…Stromal AR Role in PCa
			3.1 Stromal AR Effect on Epithelial AR Activity
			3.2 Stromal AR Effect on Metastatic Potential of PCa
				3.2.1 In Vitro Stromal-Epithelial Co-Culture System
				3.2.2 In Vivo Cre-LoxP Stromal ARKO Mouse Model
				3.2.3 Stromal AR Role in BPH as Compared to PCa
				3.2.4 Stromal AR Role Effects on S/P Cells
			3.3 Stromal AR Role in Epithelial-Mesenchymal Transition (EMT)
		4…Therapeutic Approaches Targeting Differential Roles of AR
			4.1 Targeting Stromal/Luminal Epithelial AR with ASC-J9reg
			4.2 Combination Therapy of (1) Targeting Differential AR Roles in Different Tumor Stages and (2) Targeting Differential AR Roles in Various Cell Types
		References
013Download PDF (1.6 MB)fulltext
	10 Role of Androgens and Androgen Receptor in Prostate Cancer: Genomic and Non-Genomic Actions
		Abstract
		1…Introduction
		2…Non-Genomic Effects of AR in PCa Cells
		3…Role of Androgens and AR in the Pathogenesis and Development of PCa
		4…Role of Androgens and AR in Progression of PCa
		5…Conclusions
		References
014Download PDF (1.7 MB)fulltext
	11 Mechanisms of Signal Transduction in Prostate Cancer: The Role of PI3-Kinase Pathway in Androgen Action
		Abstract
		1…PI3Kinase/AKT Pathway and Prostate Cancer
			1.1 The PI3K Family
			1.2 AKT: The Main Transducer of the PI3K Signalingsignaling Pathway
		2…Deregulation of the PI3K Pathway and Prostate Cancer
		3…Rapid Androgen Response and PI3K Crosstalk in Prostate Cancer
			3.1 Genomic vs Non-genomic: the Two ‘‘Janus Faces’’ of Androgensandrogens Action
			3.2 Androgen Receptor Subcellular Localisation: Reconcile Transcription and Transduction
			3.3 Features of Activation and Interaction Between Androgen Receptor and PI3K
			3.4 In vivo Consequences of PI3K/AKT Modulation by Androgensandrogens
		References
015Download PDF (1.7 MB)fulltext
	12 The IGF-I Axis in Prostate Cancer: The Role of Rapid Steroid Actions
		Abstract
		1…Introduction
		2…Dysregulation of the IGF AxisIGF axis and Prostate Cancer
			2.1 Experimental Studies
			2.2 Epidemiology
		3…Cross-Talk Between Sex Steroids and the IGF AxisIGF axis
			3.1 The IGF-I ReceptorIGF-I receptor and Its Signalingsignaling Pathways
			3.2 IGF-I May Affect AR Transcriptional Activity
			3.3 IGF-IR and Membrane-Initiated Effects of Sex Steroids
		4…Sex Steroids Induce IGF-IR Up-Regulation via Membrane-Initiated Effects
			4.1 Effects of Androgensandrogens
			4.2 Effects of Estrogens
			4.3 Transcription Factors Involved
			4.4 IGF-IR Positive Feed-Back Loop Through CREB Activation
		5…Conclusions and Perspectives
		Conflict of interest
		References
016Download PDF (1.7 MB)fulltext
	13 Androgen Receptor Pathway in Prostate Cancer: Old Target and New Drugs
		Abstract
		1…Introduction
		2…AR Signaling in Prostate Cancer
		3…Targeting the AR Axis with New Molecules in CRPC
			3.1 Inhibition of Steroidogenic Pathways: AbirateroneAbiraterone 	and Other Compounds
			3.2 Androgen Receptor Antagonistsantagonists: MDV-3100MDV-3100 	and Other Compounds
		4…Perspectives: From AR Inhibition to Personalized Medicine
		5…Conclusion
		References
017Download PDF (1.4 MB)front-matter
	Part III
New Tools for Steroid Receptor Analysisand Regulatory Networks
018Download PDF (2.0 MB)fulltext
	14 Quantitative Visualization of Sex Steroid Receptor Functions: AR and ER alpha
		Abstract
		1…Introduction
			1.1 Gene Regulation
			1.2 Quantitative Imaging of Cell--Cell Heterogeneity
			1.3 High-Throughput Techniques for Studying Nuclear Receptor Biology
		2…Androgen Receptor
			2.1 Basic AR Biology
			2.2 Microscopy-Based AR Assays for Mechanistic Inquiry of AR Function
			2.3 FRAP/FRET Assays for Studying the Mechanisms of AR Activation
			2.4 High-Throughput Imaging for Characterizing Pathological AR Dysfunction Moving Towards Personalized Medicine
		3…Estrogen Receptor
			3.1 Basic ER Biology
			3.2 ER Dynamics and Chromatin Remodeling by Microscopy
			3.3 Using High-Throughput Microscopy to Study ER-Coregulator Interactions
		4…Conclusions
		Acknowledgments
		References
019Download PDF (1.9 MB)fulltext
	15 Micropatterned Surfaces as Tools for the Study of the Rapid Non-genomic Actions of Steroid Receptors
		Abstract
		1…Introduction
		2…Membrane Receptors
			2.1 Classical Intracellular Steroid Receptors as Membrane-Bound Steroid Receptor
				2.1.1 Mechanisms of Rapid Non-genomic ActionNon-Genomic Action of Steroid Receptors
				2.1.2 Physiologic Significance of the Rapid Action of Steroid Hormones
		3…Rapid Action of Steroids in Mast Cells
		4…Dip-Pen Nanolithography to Study Events at the IgE Receptor
		5…Questions to be Answered
		6…Conclusions
		Acknowledgments
		References
020Download PDF (1.6 MB)back-matter
	Index
                        
Document Text Contents
Page 1

Advances in Rapid Sex-Steroid Action

Page 2

Gabriella Castoria • Antimo Migliaccio
Editors

Advances in Rapid
Sex-Steroid Action

New Challenges and New Chances
in Breast and Prostate Cancers

123

Page 135

Non-genomic Action of Steroid
Hormones: More Questions than Answers

Antimo Migliaccio, Gabriella Castoria, Antonio Bilancio,
Pia Giovannelli, Marzia Di Donato and Ferdinando Auricchio

Abstract In this chapter we aim to draw the attention of potential readers to
several aspects of our research on non-genomic action of sex steroid hormones
that have not as yet been fully investigated and might offer interesting
developments in future studies. The first aspect concerns the dependence
of phenotype on hormone concentration. The second, regards the analysis of
mechanisms responsible for the simultaneous stimulation of cell migration and
inhibition of proliferation. Besides its physiological relevance, the migration-
proliferation dichotomy might also be involved in the intermediate stages of
progression from hormone dependency to hormone independency in breast and
prostate cancers. Thirdly, the increasing number of non-reproductive cells that

A. Migliaccio � G. Castoria � A. Bilancio � P. Giovannelli �
M. Di Donato � F. Auricchio (&)
Dipartimento di Patologia Generale - II Università di Napoli,
Via L. De Crecchio, 7, 80138 Naples, Italy
e-mail: [email protected]

A. Migliaccio
e-mail: [email protected]

G. Castoria
e-mail: [email protected]

A. Bilancio
e-mail: [email protected]

P. Giovannelli
e-mail: [email protected]

M. Di Donato
e-mail: [email protected]

G. Castoria and A. Migliaccio (eds.), Advances in Rapid Sex-Steroid Action,
DOI: 10.1007/978-1-4614-1764-4_1, � Springer Science+Business Media, LLC 2012

1

Page 136

respond to steroid hormones through receptor-mediated non-genomic action
in the absence of receptor-dependent transcription challenges the classic model
of steroid hormone action as restricted to classic cell types rather than valid for
all steroid target cells. Cross talk between membrane receptors and nuclear
steroid receptors regulates nuclear steroid receptor action. An additional
cross talk occurring between membrane receptors and extra-nuclear steroid
receptors modulates to a great extent the intensity of growth factor signaling.
The observed convergence of steroid-stimulated steroid receptor heterodimers
on signaling pathways enhances signaling and offers new flexibility in the use
of steroid antagonists. Surprisingly, steroid receptor nuclear export is a crucial
step in the proliferative response mediated by non-genomic action of steroid
receptors. Finally, receptor association with signaling effectors and scaffold
proteins is the key event that initiates non-genomic proliferative, anti-apoptotic
and migratory programs. It is therefore a promising target for novel anti-cancer
therapy. Each of these aspects has been analyzed in several cell types
and in relation to different biological effects. Much more work is required to
fully evaluate their role in hormone action and their application in cancer
therapy.

Keywords Steroids � Growth factors � Non-genomic action � Protein/protein
interaction � Proliferation/migration � Steroid receptor trafficking
Abbreviations
AR androgen receptor
Crm1 chromosome region maintenance 1
EGF epidermal growth factor
EGF-R epidermal growth factor receptor
ER estradiol receptor
Fln filamin
FKHR forkhead in rhabdomyosarcoma
GR glucocorticoids receptor
MAPK mitogen activated protein kinase
MEK-1 mitogen-activated kinase kinase
NES nuclear export signal
NLS nuclear localization signal
PDGF platelet-derived growth factor
PDGF-R PDGF receptor
PI3-K phosphatidylinositol-3-kinase
PKC protein kinase C
PR progesterone receptor

2 A. Migliaccio et al.

Page 269

Index

A
Abiraterone, 155, 213–217, 220
Agonists, 46, 84, 97, 115, 170, 235,

236, 238
Androgen Receptor, 34, 145, 146, 179, 180,

182–187, 233
Androgens, 4, 7, 9, 11, 98, 145–147, 155,

156, 165–173, 180, 182–186,
188, 193, 195, 196, 199–206,
214–216, 220

Antagonists, 2, 8–11, 35, 46, 49, 115, 118,
119, 155, 201, 213, 218, 233, 234,
238, 239

arginine methylation, 13, 80, 83, 85, 86

B
BRCA1, 25, 27, 69
Breast cancer, 8, 11, 21–23, 25, 27, 33–36,

38–50, 61–67, 70, 71, 79–81,
83–89, 95–98, 100–107, 115–123,
129, 131–135, 139, 196, 200, 201,
219, 242, 256

C
Cell survival, 179, 182, 185, 189,

219, 242
Chromatin, 21–24, 27, 194, 244
Combination therapy, 44, 145, 146, 156, 157
CRPC, 146–149, 156, 213–220, 235
c-Src, 9, 21, 23, 34, 36, 38–49, 66, 85, 88, 98,

99, 101–103, 105, 106, 168, 169,
173, 186, 187, 201–206, 256, 257

D
Dip-pen nanolithography, 254, 258, 259, 263

E
Epithelial cell, 179, 183, 188
Epithelium, 34, 63, 68, 102, 146, 150, 153,

156, 173, 179, 182, 188, 196, 203
Estrogen, 33–36, 38–44, 46–50, 62–71, 81–83,

85, 86, 88, 89, 95–98, 100–106,
115–121, 123, 130–132, 134, 138,
139, 168, 170, 180, 187, 193, 195,
196, 200–206, 227, 228, 239, 241,
242, 247

Estrogen receptor, 9, 21, 23, 36, 62, 63, 69, 70,
79, 80, 89, 96–98, 102–104, 108,
115–117, 124, 129–131, 139, 170,
180, 187, 194, 201, 227, 228, 241

Estrogen receptors a
Estrogen signalling
Estrogens, 9, 79–81, 84, 89, 96, 98, 115, 116,

119, 129, 130, 132–139, 193, 195,
196, 200–206

Extra-nuclear signaling, 81, 95, 103

G
Gene regulation, 23, 28, 228–230, 233, 245
Genomic signalling, 168, 169
Glucocorticoid receptor, 36, 232, 243, 255
GPER, 115–123, 131
Growth factors, 3, 4, 9, 35, 44, 45, 62, 67,

71, 147, 152, 155, 166, 172,
193–195, 256

G. Castoria and A. Migliaccio (eds.), Advances in Rapid Sex-Steroid Action,
DOI: 10.1007/978-1-4614-1764-4, � Springer Science+Business Media, LLC 2012

267

Page 270

H
Her family receptors, 31

I
IGF axis, 193, 195–199, 206
IGF-i receptor, 62, 181, 193–195, 198
IGF-ii
Immune system, 129, 130, 138, 258
Insulin receptor, 193–195, 198

L
Ligand mixtures, 129, 130, 137

M
Mast cells, 138, 253, 254, 258, 259, 261–263
MDV-3100, 213, 214, 216, 218, 220
Membrane estrogen receptors, 124, 129, 130
Metastasis, 96–98, 100, 102–105, 107, 146,

149, 150, 155–157
MMTV, 21–24, 235, 238, 243, 244

N
Neurons, 4, 129
Non genomic signalling, 168, 169
Nongenomic, 102, 129, 130, 131, 133,

135, 139
Non-genomic action, 2, 3, 36, 67, 85, 102, 165,

168, 253–258, 263
Nonmonotonic, 129, 130, 132–134, 137
Non-nuclear action, 254
Nucleosome, 21–23

P
Palmitoylation, 80, 82–84, 88, 168, 200
Phosphatidylinositol 3-kinase, 62, 179–181,

189, 195
Pituitary, 129, 131, 132, 134, 135, 137
Post-translational modifications, 6, 45, 79, 81,

83, 85, 87, 89, 131, 168, 234
Progesterone, 9, 10, 21–25, 27, 44, 45, 95, 97,

100–102, 105, 107, 255, 258

Progesterone receptor, 9, 21, 31, 70, 83,
97, 105, 107, 122, 123, 241,
243, 255, 258

Progesterone responsive elements (pre), 23
Proliferation/migration, 2
Prostate cancer, 179, 180, 182, 183, 188,

213–215, 219, 220
Protein/protein interaction, 12
Proteolysis, 61, 62, 68–71, 82, 228

R
Rapid steroid effects, 193

S
Signal transduction, 9, 61, 62, 67, 71, 81,

82, 86, 105, 118, 168, 179, 219,
258, 261

Signaling, 3, 5, 6, 8–12, 21, 27, 34–36,
38–48, 66, 67, 69–71, 79–88,
95, 96, 98, 99, 101–107, 115,
117–121, 123, 130–134, 136–138,
145–149, 154, 156, 157, 179–184,
189, 195–201, 207, 213–215, 220,
228, 235, 241, 242

Single cell analysis, 254
Src kinase, 38, 43, 45, 61, 62, 66, 81, 98, 168,

183, 186
Steroid receptor trafficking, 2
Steroids, 44, 79, 95–102, 104–107, 185, 186,

254–258, 264
Stroma, 145–148, 151–154, 156, 157, 173

T
Therapeutic resistance, 31

U
Ubiquitin, 27, 61–63, 68–70, 82, 234

X
Xenoestrogens, 133, 134, 136–139, 203

268 Index

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