Molecular Basis of Breast Cancer: Prevention and Treatment

459 Pages·2004·56.398 MB·English

by  Jose Russo MD, FACP, Irma H. Russo MD, FACP (auth.)

Jose Russo · Irma H. Russo
Molecular Basis of Breast Cancer
Prevention and Treatment
Springer-Verlag Berlin Heidelberg GmbH
Jose Russo
Irma H. Russo
o ecular Basis
of Breast Cancer
Prevention and Treatment
With 338 Figures and 63 Tables
i
Springer
ISBN 978-3-642-62270-0 ISBN 978-3-642-18736-0 (eBook)
DOI 10.1007/978-3-642-18736-0
Jose Russo MD, FACP Library of Congress Cataioging-in.Publication Data
Irma H. Russo, MD, FACP Russo, Iose. Molecular basis of breast cancer: prevention and
treatment/J. Russo, Irma H. Russo. p.; cm. Includes biblio·
graphical references and indeL ISBN J-S40-00J91-6 (alk paper)
Breasl Cancer Research Laboralory
1. Breul-Cancer-Molecular aspeclS. 1. Breast-Cancer-Patho
Fox Chase Cancer Cenler
genesis. 1. Russo, Irma H. II. Title. IDNLM: 1. Breast Neo
333 Cottman Avenue plasm-prevention & conlroL 1. Breast Neoplasms-therapy. WP
Philadelphia,PA 19111 870 R969m 10041 RC180.B8R871004 616.99'449071-dcl
USA
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Preface
During the past 30 years we have witnessed the emer book, whose goal is to comprehensively review in ten
gence of new disciplines whose contribution to the chapters the fundamental knowledge on breast can
understanding of the biology of breast cancer have cer. The opening chapter links epidemiology, influ
been enormous. Advances in the field of steroid hor ence of geographic and environmental exposures on
mone nuclear receptors, which control the expression cancer incidence to the development of the organ and
of genetic programs involved in cellular processes its role in cancer initiation. Central to this approach
that are essential for normal and aberrant cell is the endocrine control of breast development, the
growth, have been major contributors to the therapy relationship of cell proliferation with the presence of
and prevention of hormone-dependent cancers. The steroid hormone receptors in the breast epithelium,
discoveries of the association of hereditary breast and finally the importance of full differentiation as a
cancers with mutations in the BRCAl and BRCA2 tool for protecting the breast from developing cancer.
genes, and the concept that they essentially represent Reported are studies of the pathogenesis of breast
a continuum of mutations with different degrees of cancer that have elucidated the site of origin of breast
penetrance within given families, have added consid cancer and have been validated by in vitro experi
erable understanding to the molecular basis of breast mentation. The utilization of these models for the
cancer. These advances have been hastened by the use analysis of molecular and genetic changes in the ini
of recombinant DNA technology, which has become a tiation and progression of breast cancer has uncov
revolutionary tool for probing the human genome. ered key processes during the immortalization and
This explosion in knowledge on the hormonal and transformation of human breast epithelial cells and
genetic basis of breast cancer, and considerable ad genetic heterogeneity within single lesions. A chapter
vances in its early detection and therapeutic modali has been devoted to animal models for human breast
ties have awakened great hopes for the conquest of cancer, pathological classification of rat mammary
this disease. However, they have not been fulfilled as tumors, and genetically engineered mice model.
yet, since the mortality caused by this disease has re These studies are complemented with in vitro mod
mained almost unchanged for the past five decades, a els for human breast cancer, unifying various aspects
dismal picture worsened by the gradual increase in of growth properties of normal and neoplastic breast
breast cancer incidence reported in most Western epithelial cells in vitro, transformation of cells with
countries and in societies that are becoming western carcinogens and oncogenes. This knowledge is essen
ized. tial for determining the functional relevance of ge
The realization that traditional developmental nomic changes in cancer initiation and progression
concepts need to provide the necessary framework and for developing strategies for breast cancer pre
for the interpretation of data generated by these vention.
modern techniques, in order to complete the still un
finished puzzle that the etiology, pathogenesis and Jose Russo, MD, FCAP
progression of cancer represent, led us to design this Irma H. Russo, MD, FCAP
Acknowledgements
I am a part of all that I have met We pay tribute to the visionaries that ignited our
imagination and fed our hunger for knowledge: Dr.
uLYSSES Alfred, Lord Tenny on Julian Echave Llanos and Dr. Mario H. Burgos opened
for us the magnificent doors of science and experi
mentation at the School of Medical Sciences in Men
doza, Argentina. Dr. Michael Brennan of the Michi
gan Cancer Foundation provided a fertile ground for
developing seminal ideas. In the same institution a
valued colleague, Dr. Herbert Soule, through the de
velopment of breast epithelial cell lines provided in
valuable tools for the scientific community to ad
vance the understanding of hormonal regulation of
cell growth and cell transformation. And last, but not
least, the expertise and support of the staff members
of the Fox Chase Cancer Center is a continuous
source of encouragement.
We are indebted to our postdoctoral associates
who through the years have been contributors to the
publications reported or referenced in this book,
among them Drs. A. Adesina, M. E. V. Alvarado, F. Ba
solo, B. Bove, G. Calaf, D. Ciocca, G. Fontanini, S. Higa,
T.-Y. Ho, Y. Huang, X. Jiang, F. Martinez, J. Ochieng,
A.M. Salicione, I. D. C. Silva, N. So hi, L. K. Tay, and
P.-L. Zhang.
We acknowledge the special contribution of Drs.
Hasan M. Lareef and Gabriela Balogh in providing
data supporting the work presented in Chapter 4, Dr.
Yun Fu Hu in writing and compiling the numerous
references of Chapter 9, and Dr Pramod Srivastava
for data presented in Chapter 10. We are also grateful
for the assistance of Dr. Fathima Sheriff for perform
ing literature searches, Ms. Joan Levin for typing ta
bles and references for this book, and Ms. Patricia A.
Russo for her artwork contribution in Chapter 2.
Contents
2.10 Extracellular Matrix Protein Expression
1 Epidemiological Considerations in the Normal Breast . . . . . . . 32
in Breast Cancer 2.10.1 Angiogenic Index
in the Lobular Structures 32
1.1 Introduction . . . . . . . . . . . 1 2.1 0.2 Elastin in the
1.2 Geographical Influences . . . . 1 Lobular Structures . . . . . . . . . 34
1.3 Radiation as an Etiologic Agent 2 2.10.3 Tenascin in the
1.4 Electromagnetic Fields . . 2 Lobular Structures . . ... 35
1.5 Environmental Pollutants 3 2.11 Genomic Profile of
1.6 Reproductive Factors . . . 3 Lobular Structures in Nulliparous
1.7 Environmental Exposures and Parous Women's Breasts . . . . . . . . 36
at a Young Age that Increase 2.12 Novel Differentiation-Associated
the Risk of Breast Cancer . . 4 Serpin is Upregulated During
1.7.1 Endocrinological Milieu 4 Lobular Development . . . . . . . . . 40
1.7.2 Smoking ........ . 4 2.13 Mammary-Derived Growth Inhibitor . 45
1.7.3 Alcohol as a Neuroendocrine 2.14 Conclusions . 45
Disruptor ......... . 5 References . . . . . . . . . . . . . . . . . . . . 46
1.7.4 Effect of Light on Puberty
and Breast Cancer Risk 5
1.8 Conclusions 6 3 Endocrine Control
References . . . . . . . . . . . . . . . . 6 of Breast Development
3.1 Introduction . . . . . . . . . . . . . . . 49
2 The Breast as a Developing Organ 3.2 Steroid Receptors, Cell Proliferation,
and Breast Differentiation . . . . . . . 51
2.1 Introduction . . . . . . . . . . . . . . 11 3.2.1 Relationship of Proliferating
2.2 Prenatal and Perinatal Development 12 and ERa-Positive Cells
2.3 Postnatal Development . . 15 in the Human Breast . . . . . . . . 53
2.4 Pregnancy . . . . . . . . . 22 3.2.2 Cell Proliferation, ERa,
2.5 Postlactational Changes . 26 and PgR Content in the
2.6 The Menopausal Breast . . 26 Rat Mammary Gland 53
2.7 Parenchyma-Stroma Relationship . 29 3.2.3 Biological Significance 55
2.8 Genetic Influences 3.3 Human Chorionic Gonadotropin
in Breast Development . . . . . . . 30 as a Differentiating Agent in the
2.9 Cell Proliferation and Hormone Human Breast and in the
Receptors in Relation to Breast Structure . 31 Rodent Mammary Gland . . . . . . . . .. 57
3.3.1 Evidence for a Receptor 4.3 Role of Estrogens in Human
for Human Chorionic Breast Proliferation . . . . . . . . . . . 94
Gonadotropin in Human 4.4 Estrogens in Human Breast
Breast Epithelial Cells . . .... 57 Carcinogenesis . . . . . . . 95
3.3.2 Human Chorionic 4.4.1 Receptor-Mediated Pathway 96
Gonadotropin Receptor 4.4.2 Oxidative Metabolism
in the Rat Mammary Gland . 60 of Estrogen . . . . . . . . . 98
3.3.3 Biological Significance 4.4.2.1 Estrogen as Mutagenic
of the LH/hCG Receptor . 60 Agents . . . . . . . . . . . . . . 100
3.4 Effect of Human Chorionic Gonadotropin 4.4.2.2 The Mechanism by Which
on Human Breast Epithelial Cells . . . . . 61 Estrogens Induce Mutations . . . 100
3.4.1 Effect on Protein Synthesis 4.4.2.3 Additional Factors
and In Vitro Translational Contributing to the Carcinogenic
Products of mRNA .... 61 Effect of Estrogen ...... 100
3.4.2 Effect of Human Chorionic 4.4.3 Estrogens as Inducers
Gonadotropin Treatment of Aneuploidy . . . . . . . 101
on Inhibin Synthesis . . . . . . . . 64 4.5 Biological Demonstration
3.4.3 Effect of Hormones on the That Estrogens Are Carcinogenic
Proliferative Activity of in the Human Breast . . . . . . 102
Cultured Normal and Neoplastic 4.5.1 The Proof of Principle 102
Human Breast Epithelial Cells . 68 4.5.2 The In Vitro Model
3.4.4 Biological Significance of Cell Transformation 102
of the hCG-Inhibin Pathway . 69 4.5.2.1 Transformation Effect
3.5 Homeobox Genes' Expression of Estrogen in MCF-lOF Cells 102
and Their Modulation by Human 4.5.2.2 Transformation Effect
Chorionic Gonadotropin in Human of the Estrogen Metabolites . 106
Breast Epithelial Cells . . . . . . . . . . . 71 4.5.2.3 Role of Antiestrogens
3.5.1 Class I Homeobox Gene in the Expression of the
Expression in Human Breast Transformation Phenotype . 109
Epithelial Cell Lines . . . . . . 72 4.5.2.4 Detection of Estrogen
3.5.2 Human Chorionic Gonadotropin Receptors in MCF I OF-Cells 111
Modulates Expression of 4.5.2.5 Evidence for a Role
Homeobox Genes . . . . . . . . . 73 of ERP and Metabolic
3.5.3 Human Chorionic Gonadotropin Activation of Estrogen in the
and HOXA2 Inhibit AP-1 74 Transformation of Human
3.6 Human Chorionic Gonadotropin Breast Epithelial Cells . . . . . . 112
and Histone Acetylation 78 4.5.3 Genomic Changes Induced
3.7 Conclusions . 80 by Estrogen and Its Metabolites
References . . . . . . . . . . . . . 81 in Human Breast Epithelial Cells 113
4.5.4 Other Genomic Changes
Induced by Estrogen and Its
Metabolites in the Transformation
of Human Breast Epithelial Cells 118
4.1 Introduction . . . . . . . . 89 4.5.5 Chromosomal Alterations
4.2 Sources of Estrogens Induced by Estrogen and Its
in Human Breast Tissue . 90 Metabolites . . . . . . . . . . . . 124
4.6 A Unified Concept in the Role 5.5.3 Example of Breast Cancer
of Estrogen in Breast Cancer 128 Genetic Heterogeneity
References . . . . . . . . . . . . . . . . 128 Revealed by Laser Capture
Microdissection Technique 172
5.6 Summary and Conclusions . . . . . 175
References . . . . . . . . . . . . . . . . . . . . . 176
5.1 Introduction . . . . . . . . . . . . . 137
5.2 The Site of Origin of Breast Cancer 137
5.3 Supporting Evidence for the Site
of Origin of Breast Cancer 139 6.1 Introduction . . . . . . . . . . . 181
5.3.1 In Vitro Studies . . . . . 139 6.2 General Concepts . . . . . . . . 181
5.3.2 Breast Architecture as a 6.3 Chemically-Induced Mammary
Determining Factor in the Tumorigenesis . . . . . . . . . . 182
Susceptibility of the Human 6.4 Radiation-Induced Mammary
Breast to Cancer . . . . . . . 142 Tumorigenesis . . . . . . . 183
5.3.3 Specific Considerations on the 6.5 Genetic Background and
Relation Between Lobular Mammary Carcinogenesis . . . . . . . 185
Development and Familial 6.6 Pathogenesis of Rat Mammary Tumors 185
Breast Cancer-Related Genes 147 6.7 Mammary Gland Differentiation as a
5.3.4 Unifying Concepts . . . . . 149 Modulator of Carcinogenic Response 191
5.4 Molecular Changes in the Initiation 6. 7.1 Cell of Origin of Rat
and Progression of Breast Cancer 150 Mammary Carcinomas 195
5.4.1 Differential Expression 6.7.2 Cell Kinetics and Mammary
of Human Ferritin H Chain Carcinogenesis . . 199
Gene and Breast Cancer ... 150 6.7.3 Role of the Stroma
5.4.2 SlOOP Calcium-Binding in the Pathogenesis
Protein as a Marker of of Mammary Cancer . . . . . . . 204
Cancer Initiation . . . . . . 153 6.8 Pathological Classification
5.4.3 Role of Intracellular Ca2+ of Rat Mammary Tumors . . . . . . . . . 209
During Cell Immortalization 6.8.1 Epithelial Neoplasms ....... 210
and Cell Transformation ..... 161 6.8.1.1 Intraductal Papilloma . 210
5.4.4 The Role of Ca Intracellular 6.8.1.2 Papillary Cystadenoma . 210
and S1 00 Protein Expression 6.8.1.3 Adenoma . . . . . . . . 210
in the Formation of Microcal 6.8.1.4 Precancerous Lesions:
cifications in Preneoplastic Intraductal Proliferation . . . 210
and Neoplastic Lesions 6.8.1.5 Carcinoma In Situ . 212
of the Breast . . . . . . . . . . . 164 6.8.1.6 Invasive Ductal
5.5 Genetic Changes Associated Carcinomas . . . . . 212
with Initiation and Progression 6.8.2 Stromal Neoplasms ... . 216
of Breast Cancer . . . . . . . . . 167 6.8.2.1 Fibroma .. 216
5.5.1 Laser Capture Microdissection 168 6.8.2.2 Fibrosarcoma .. 216
5.5.2 Microsatellite Instability 6.8.3 Epithelial-Stromal Neoplasms .. 217
and Loss of Heterozygosity 6.8.3.1 Fibroadenoma . 217
in Microdissected Lesions 6.8.3.2 Carcinosarcoma 218
of the Breast . . . . . . . . . . . 171 6.8.4 Nonneoplastic Lesions . 218