Breast Cancer: Cellular and Molecular Biology

Cancer Treatment and Research

WILLIAM L MCGUIRE, series editor

Livingston RB (ed): Lung Cancer 1. 1981. ISBN 90-247-2394-9. Bennett Humphrey G, Dehner LP, Grindey GB, Acton RT (eds): Pediatric Oncology 1. 1981.

ISBN 90-247-2408-2. DeCosse JJ, Sherlock P (eds): Gastrointestinal Cancer 1. 1981. ISBN 90-247-2461-9. Bennett JM (ed): Lymphomas 1, including Hodgkin's Disease. 1981. ISBN 90-247-2479-1. Bloomfield CD (ed): Adult Leukemias 1. 1982. ISBN 90-247-2478-3. Paulson DF (ed): Genitourinary Cancer 1. 1982. ISBN 90-247-2480-5. Muggia FM (ed): Cancer Chemotherapy 1. ISBN 90-247-2713-8. Bennett Humphrey G, Grindey GB (eds): Pancreatic Tumors in Children. 1982. ISBN 90-247-2702-2. Costanzi JJ (ed): Malignant Melanoma 1. 1983. ISBN 90-247-2706-5. Griffiths CT, Fuller AF (eds): Gynecologic Oncology. 1983. ISBN 0-89838-555-5. Greco AF (ed): Biology and Management of Lung Cancer. 1983. ISBN 0-89838-554-7. Walker MD (ed): Oncology of the Nervous System. 1983. ISBN 0-89838-567-9. Higby DJ (ed): Supportive Care in Cancer Therapy. 1983. ISBN 0-89838-569-5. Herberman RB (ed): Basic and Clinical T\lmor Immunology. 1983. ISBN 0-89838-579-2. Baker LH (ed): Soft Tissue Sarcomas. 1983: ISBN 0-89838-584-9. Bennett JM (ed): Controversies in the Management of Lymphomas. 1983. ISBN 0-89838-586-5. Bennett Humphrey G, Grindey GB (eds): Adrenal and Endocrine Tumors in Children. 1983.

ISBN 0-89838-590-3. DeCosse JJ, Sherlock P (eds): Clinical Management of Gastrointestinal Cancer. 1984.

ISBN 0-89838-601-2. Catalona WJ, Ratliff TL (eds): Urologic Oncology. 1984. ISBN 0-89838-628-4. Santen RJ, Manni A (eds): Diagnosis and Management of Endocrine-related Tumors. 1984.

ISBN 0-89838-636-5. Costanzi JJ (ed): Clinical Management of Malignant Melanoma. 1984.

ISBN 0-89838-656-X. Wolf GT (ed): Head and Neck Oncology. 1984. ISBN 0-89838-657-8. Alberts DS, Surwit EA (eds): Ovarian Cancer. 1985. ISBN 0-89838-676-4. Muggia FM (ed): Experimental and Clinical Progress in Cancer Chemotherapy. 1985.

ISBN 0-89838-679-9. Higby DJ (ed): The Cancer Patient and Supportive Care. 1985. ISBN 0-89838-690-X. Bloomfield CD (ed): Chronic and Acute Leukemias in Adults. 1985. ISBN 0-89838-702-7. Herberman RB (ed): Cancer Immunology: Innovative Approaches to Therapy. 1986.

ISBN 0-89838-757-4. Hansen HH (ed): Lung Cancer: Basic and Clinical Aspects. 1986.

ISBN 0-89838-763-9. Pinedo HM, Verweij J (eds): Clinical Management of Soft Tissue Sarcomas. 1986.

ISBN 0-89838-808-2. Higby DJ (ed): Issues in Supportive Care of Cancer Patients. 1986. ISBN 0-89838-816-3. Surwit EA, Alberts DS (eds): Cervix Cancer. 1987. ISBN 0-89838-822-8. Jacobs C (ed): Cancers of the Head and Neck. 1987. ISBN.0-89838-825-2. MacDonald JS (ed): Gastrointestinal Oncology. 1987. ISBN 0-89838-829-5. Ratliff TL, Cata10na WJ (eds): Genitourinary Cancer. 1987. ISBN 0-89838-830-9. Nathanson L. (ed): Basic and Clinical Aspects of Malignant Melanoma. 1987. ISBN 0-89838-856-2. Muggia FM (ed): Concepts, Clinical Developments, and Therapeutic Advances in Cancer Chemo-

therapy. 1987. ISBN 0-89838-879-5.

Breast Cancer: Cellular and Molecular Biology

edited by

MARC E. LIPPMAN

and

ROBERT B. DICKSON National Cancer Institute

~. 1988 KLUWER ACADEMIC PUBLISHERS 11111 BOSTON I DORDRECHTI LONDON .,~

Distributors

for the United States and Canada: Kluwer Academic Publishers, 101 Philip Drive, Assinippi Park, Norwell, MA 02061 for the UK and Ireland: Kluwer Academic Publishers, Falcon House, Queen Square, Lancaster LAI lRN, UK for all other countries: Kluwer Academic Publishers Group, Distribution Center, P.O. Box 322,3300 AH Dordrecht, The Netherlands

Library of Congress Cataloging in Publication Data

Breast cancer: cellular and molecular biology/edited by Marc E. Lippman, Robert B. Dickson.

p. cm. - (Cancer treatment and research) Includes bibliographies and index. ISBN-13: 978-1-4612-8975-3 e-ISNB-13: 978-1-4613-1733-3 DOl: 10.1007/978-1-4613-1733-3 1. Breast-Cancer. 2. Breast-Pathophysiology.

3. Breast-Cytopathology. I. Lippman, Marc E., 1945-II. Dickson, Robert B. (Robert Brent), 1952- . III. Series.

[DNLM: 1. Breast Neoplasms-physiopathology. 2. Cell Transformation, Neoplastic. 3. Epithelium-physiopathology. 4. Estrogens-physiology. 5. Growth Substances-physiology. WI CA693/WP 870 B8232} RC280 B8B6657 1988 616. 99'44907-dcI9 DNLM/DLC for Library of Congress

Copyright

© 1988 by Kluwer Academic Publishers, Boston. Softcover reprint of the hardcover 1st edition 1988

87-38322 CIP

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or trallsmitted in any form or by any means, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publishers, Kluwer Academic Publishers, 101 Philip Drive, Assinippi Park, Norwell, MA 02061

Contents

Foreword ix

Preface xi

List of Contributors xv

1. Human Mammary Epithelial Cells in Culture: Differentiation and Transformation MARTHA R. STAMPFER and JACK C. BARTLEY 1

2. Heterogeneity of Genetic Alterations in Primary Human Breast Tumors IQBAL UNNISA ALI, ROSETTE LIDEREAU, and ROBERT CALLAHAN 25

3. Different Mechanisms are Responsible for Oncogene Activation in Human Mammary Neoplasia MATTHIAS H. KRAUS, PIER PAOLO DI FIORE, JACAL YN H. PIERCE and STUART A. AARONSON 49

4. Identification of Oncogenes in Breast Tumors and their Effects on Growth and Differentiation B. GRONER, N.E. HYNES, S. KOZMA, S. REDMOND, S. SAURER, M. SCHMITT-NEY, R. BALL, E. REICHMANN, C. SCHONENBERGER and A.C. ANDRES 67

5. Epidermal Growth Factor Receptors in Human Breast Cancer ADRIAN L. HARRIS and STEWART NICHOLSON 93

6. Control of Human Breast Cancer by Estrogen, Growth Factors, and Oncogenes ROBERT B. DICKSON and MARC E. LIPPMAN 119

VI

7. Actions of Pituitary Prolactin and Insulin-like Growth Factor II in Human Breast Cancer ROBERT P.c. SHIU, LEIGH C. MURPHY, YVONNE MY AL, THOMAS C. DEMBINSKI, DEBORAH TSUYUKI, and BARBARA M. IW ASIOW 167

8. Structure and Function of the PS2 Gene and Estrogen Receptor in Human Breast Cancer Cells G. STACK, V. KUMAR, S. GREEN, M. PONGLIKITMONGKOL, M. BERRY, M.C. RIO, A.M. NUNEZ, M. ROBERTS, C. KOEHL, P. BELLOCQ, B. GAIRARD, R. RENAUD, and P. CHAMBON 185

9. The 52K Cathepsin-D of Breast Cancer: Structure, Regulation, Function and Clinical Value HENRI ROCHEFORT, PATRICK AUGEREAU, FRANCOISE CAPO NY , MARCEL GARCIA, VINCENT CA V AILLES, GILLES FREISS, MURIEL MORIS SET and FRANCOISE VIGNON 207

10. Tumor Invasion and Metastases: Biochemical Mechanisms LANCE A. LIOTTA and MARY L. STRACKE 223

11. Factors Regulating Basement Membrane Invasion by Tumor Cells E.W. THOMPSON, R. REICH, G.R. MARTIN and A. ALBINI 239

12. Regulation of Development of the Normal Mammary Gland by Hormones and Growth Factors BARBARA K. VONDERHAAR 251

13. MMTV as a Model for Gene Expression in Mammary Tissue GORDON L. HAGER 267

14. The Activation of Cellular Oncogenes by Proviral Insertion in Murine Mammary Cancer ROEL NUSSE 283

15. Steroid Hormone Regulation of Cultured Breast Cancer Cells PHILIPPA D. DARBRE and ROGER J.B. KING 307

16. The Role of Epidermal Growth Factor in Normal and Neoplastic Growth of Mouse Mammary Epithelial Cells TAKAMI OKA, OSAMU TSUTSUMI, HIROHISA KURACHI, and SHIGERU OKAMOTO 343

17. Tumor-associated Growth Factors in Malignant Rodent and Human Mammary Epithelial Cells

vn

DAVID S. SALOMON and WILLIAM R. KIDWELL 363

Index 391

Cancer Treatment and Research

Foreword

Where do you begin to look for a recent, authoritative article on the diagnosis or management of particular malignancy? The few general oncology text­books are generally out of date. Single papers in specialized journals are informative but seldom comprehensive; these are more often preliminary reports on a very limited number of patients. Certain general journals fre­quently publish good in-depth reviews of cancer topics, and published sym­posium lectures are often the best overviews available. Unfortunately, these reviews and supplements appear sporadically, and the reader can never be sure when a topic of special interest will be covered.

Cancer Treatment and Research is a series of authoritative volumes which aim to meet this need. It is an attempt to establish a critical mass of oncology literature covering virtually all oncology topics, revised frequently to keep the coverage up to date, easily available on a single library shelf or by a single personal subscription.

We have approached the problem in the following fashion. First, by divid­ing the oncology literature into specific subdivisions such as lung cancer, genitourinary cancer, pediatric oncology, etc. Second, by asking eminent authorities in each of these areas to edit a volume on the specific topic on an annual or biannual basis. Each topic and tumor type is covered in a volume appearing frequently and predictably, discussing current diagnosis, staging, markers, all forms of treatment modalities, basic biology, and more.

In Cancer Treatment and Research, we have an outstanding group of editors, each having made a major commitment to bring to this new series the very best literature in his or her field. Kluwer Academic Publishers has made an equally major commitment to the rapid publication of high quality books, and worldwide distribution.

Where can you go to find quickly a recent authoritative article on any major oncology problem? We hope that Cancer Treatment and Research pro­vides an answer.

WILLIAM L. McGUIRE Series Editor

Preface

Marc E. Lippman, M.D., and Robert B. Dickson, Ph.D.

The past few years have witnessed a revolution in our understanding of the biology of breast cancer. In part, this is due to the availability of biochemical and molecular biological techniques to allow identification, characterization, and experimental perturbation of potent regulatory molecules such as recep­tors, proteases, growth factors, and oncogenes. A considerable number of researchers utilize fresh human clinical material, normal and human breast cancer cell lines in vitro, and xenograft tumors in vivo in the athymic (or nude) mouse. Others, however, employ a mouse model system whereby a tumor virus known as mouse mammary tumor virus (MMTV), carried in the milk or through the germ line, triggers mouse mammary cancer. In this volume we present both areas of investigation: first, studies on human mammary cancer, then second, work on mouse breast cancer induced by MMTV. We believe that by presenting both kinds of studies we provide a book suitable for a wide readership of postdoctoral and medical fellows and researchers.

The first chapter, by Martha Stampfer and Jack Bartley, presents the state of the art in culture of normal human mammary epithelial cells. Studies on cancer should always use normal tissue as a reference point in order to high­light tumor-specific versus simply proliferation-specific cellular characteristics. This chapter also presents information on properties of carcinogen-treated mammary epithelial cells. The second chapter, continuing in the theme of human breast cancer, studies rearrangements in human genes which might be associated with loss of cancer repressor gene. In addition to possible import­ance of exposure to chemical carcinogens, breast cancer risk is known to be associated with a significant genetic component. Igbal Unissa Ali and Robert Callahan propose that inherited rearrangements of chromosome 11 could be one of these genetic factors. The third chapter, by Matthias Kraus and co­workers continues the theme of genetic alterations in cancer patients by reporting on the specific oncogenes found activated in breast cancers them­selves. Alterations in c-H-ras and erbB-2 oncogenes may be involved in pro­gression of breast cancer to more malignant forms. In the fourth chapter, Bernd Groner and co-workers explore other functions of activated oncogene expression, This chapter analyzes the effects of oncogenes on the differentiated state of breast tissue. Oncogenes have proven powerful switches to dediffer-

xii

entiate or despecialize the secretory epithelium. The fifth chapter, by Adrian Harris and Stewart Nicholson reports on studies of the receptor for epidermal growth factor (EGF) in breast cancer. This is also a proto-oncogene known as c-erbB, and its expression appears to be a new tumor marker for the poor pro­gnosis breast cancer patients. The sixth chapter, by ourselves, addresses the possible role of polypeptide growth factors in the local autocrine and para­crine control of breast cancer. Growth factors TGFa, IGF-I, and PDGF and the growth inhibitory TGFB are under regulation by estrogen and anti-estrogen control in hormone responsive breast cancer. The seventh chapter, by Robert Shiu, extends the scope of endocrine control of breast cancers to include direct effects by pituitary hormones such as IGF-II and prolactin. The thesis of this chapter is that host factors, in addition to circulating estrogen, control the progression of breast cancer. The eighth chapter, by Gary Stack and co­workers, addresses the molecular biology of the estrogen receptor itself and of a major estrogen regulated protein known as pS2. The studies of this group have begun to define the biochemical and molecular details of estrogen re­ceptor-gene interactions. The ninth chapter, by Henri Rochefort and co­workers, examines another estrogen receptor regulated protein, a secreted cathepsin. This protein may have a role in degrading basement membrane which encapsulates the tumor. The tenth chapter, by Lance Liotta and Mary Stracke further addresses this area of tumor-host interactions. They sum­marize data demonstrating that metastasis requires a cancer cell to bind to the basement membrane through its receptors for laminin. Next, elaboration of various proteolytic enzymes allows the cell to chew its way through the base­ment membrane, and seed other bodily tissues in advanced stages of the disease. The eleventh chapter, by Erik Thompson and co-workers, extends this theme by reporting in detail on the structure of laminin and on an in vitro basement membrane model system for analysis of the invasive characteristics of tumor cells.

The twelfth chapter begins an in-depth consideration of the mouse as a model system for breast cancer. Barbara Vonderhaar describes the organo­genesis of breast tissue. She points out that growth factors such as EGF and TGFa, and the expression of the EGF receptor may be critical regulators of normal development of the mouse mammary gland. The thirteenth chapter, by Gordon Hagar, characterizes the MMTV virus itself. This virus integrates into the host genome and promotes transcription of host genes. Roel Nusse, in the fourteenth chapter, further examines some of these cellular genes activated by MMTV. They appear to be a new class of oncogenes, at least one of which is closely related to a fibroblast growth factor. In the fifteenth chapter, Philippa Darbre and Roger King address the question of loss of hormonal controls during the malignant progression of mouse mammary cancer cells in vitro. They note that loss of hormonal control can occur by other means than by loss of the steroid hormone receptors. In particular, methylation of genes may make them refractory to hormonal control. Takami Oka and co-workers, in the sixteenth chapter, continues analysis of the role of

xiii

growth factors in mouse mammary tumors. He reports that salivary gland­derived EGF is a critical, host supplied hormonal factor which is necessary for spontaneous tumor formation. Finally, David Salomon and William Kidwell, in the seventeenth chapter, note that rodent mammary tumors themselves produce growth factors, in striking similarity to human breast cancer. They further note that growth factor production may be a normal function of mam­mary epithelial cells since a plethora of growth factors are found in milk.

We believe that, taken together, these chapters provide a comprehensive, up-to-date synthesis of current thinking on the cellular and molecular biology of breast cancer. We hope this volume provides a stimulus for future basic and clinical research in breast cancer. Perhaps, treatments of the future will be developed out of some of the newly elucidated concepts in growth control presented herein.

Marc E. Lippman, M.D. Robert B. Dickson, Ph.D

List of Contributors

AARONSON, Stuart A., Laboratory of Cellular and Molecular Biology, National Institutes of Health, Building 37, Room lE24, Bethesda, Mary­land 20892 U.S.A.

ALBINI, A., Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, Building 6, Room 224, Bethesda, Maryland 20892 U.S.A.

ALI, I.U., Laboratory of Tumor Immunology and Biology, Building 10, Room 8B07, National Cancer Institute, Bethesda, Maryland 20892 U.S.A.

ANDRES, A.c., Ludwig Institute for Cancer Research, Bern Branch, Insel­spital, CH-301O Bern SWITZERLAND

AUGEREAU, Patrick, INSERM Unit 148, 60, rue de Navacelles, 34100 Montpellier, FRANCE

BALL, R., Ludwig Institute for Cancer Research, Bern Branch, Inselspital, CH-301O Bern SWITZERLAND

BARTLEY, Jack C., Lawrence Berkeley Laboratory, Building 934, Berke­ley, California 94720 U.S.A.

BELLOCQ, J.P., Institut de Chimie Biologique, Faculte de Medecine, 11, rue Humann, 67085 Strasbourg Cedex FRANCE

BERRY, M., Institut de Chimie Biologique, Faculte de Medecine, 11, rue Humann, 67085 Strasbourg Cedex FRANCE

CALLAHAN, Robert, Laboratory of Tumor Immunology and Biology, Na­tional Cancer Institute, National Institutes of Health, Building 10, Room 8B07, Bethesda, Maryland 20892 U.S.A.

CAPONY, Francoise, INSERM Unit 148,60, rue de Navacelles, 34100 Mont­pellier FRANCE

CAV AILLES, Vincent, INSERM Unit 148, 60, rue de Navacelles, 34100 Montpellier FRANCE

CHAMBON, Pierre, Laboratorie de Genetique Moleculaire des Cucaryotes du CNRS, Unite 184 de Biologie Moleculaire et de Genie Genetique de l'INSERM, Institut de Chimie Biologique, Faculte de Medecine, 11, rue Humann, 67085 Strasbourg-Cedex FRANCE

DARBRE, Philippa, D., Imperial Cancer Research Fund, Lincoln's Inn Fields, London WC2A 3PX UNITED KINGDOM

DEMBINSKI, Thomas C., Department of Physiology, Faculty of Medicine,

XVI

University of Manitoba, Winnipeg, Manitoba R3E OW3 CANADA DICKSON, Robert, Medical Breast Cancer Section, Medicine Branch, Na­

tional Cancer Institute, Building 10, Room 12N226, Bethesda, MD 20892 U.S.A.

DI FIORE, Pier Paolo, Molecular Biology Section, Laboratory of Cellular and Molecular Biology, National Cancer Institute, Building 37, Room lE24, Bethesda, Maryland 20892 U.S.A.

FREISS, Gilles, Unite Hormones et Cancer (U 148) INSERM, University of Montpellier - 60, rue de Navacelles, 34090 Montpellier FRANCE

GAIRARD, B., Service Gynecologique et Obstetrical, Hopital de Haute­pierre, 67091 Strasbourg FRANCE

GARCIA, Marcel, INSERM Unit 148,60, rue de Navacelles, 34100 Mont­pellier FRANCE

GREEN, S., Institut de Chimie Biologique, Faculte de Medecine, 11, rue Humann, 67085 Strasbourg-Cedex FRANCE

GRONER, Bernd, Ludwig Institute for Cancer Research, Bern Branch, Inselspital, CH-301O Bern SWITZERLAND

HAGER, Gordon, L., Hormone Action and Oncogenesis Section, Labora­tory of Experimental Carcinogenesis, National Cancer Institute, Build­ing 37, Room 3C19, Bethesda, Maryland 20892 U.S.A.

HARRIS, Adrian, L., University Departments of Clinical Oncology and Sur­gery, Cancer Research Unit, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP UNITED KINGDOM

HYNES, N.E., Ludwig Institute for Cancer Research, Bern Branch, Insel­spital, CH-301O Bern, SWITZERLAND

IWASIOW, B., Department of Physiology, Faculty of Medicine, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba R3E OW3 CANADA

KIDWELL, William R., Laboratory of Tumor Immunology and Biology, Division of Cancer Biology and Diagnosis, National Cancer Institute, National Institutes of Health, Building 10, Room 5B39, Bethesda, Mary­land 20892 U.S.A.

KING, RobertJ.B., Imperial Cancer Research Fund, P.O. Box 123, Lincoln's Inn Fields, London WC2A 3PX, ENGLAND

KOEHL, c., Laboratoire de Genetique Molecular des Eucaryotes du CNRS, Unite 148, de Biologie Moleculaire et de Genie Genetique de l'INSERM Institut de Chimie Biologique, Faculte de Medecine, 67085 Strasbourg, Cedex FRANCE

KOZMA, S., Ludwig Institute for Cancer Research, Bern Branch, Insel­spital, CH-301O Bern, SWITZERLAND

KRAUS, Matthias H., Molecular Biology Section, Laboratory of Cellular and Molecular Biology, National Cancer Institute, Building 37, Room lE24, Bethesda, Maryland 20892 U.S.A.

KUMAR, V., Institut de Chimie Biologique, Faculte de Medecine, 11, rue Humann, 67085 Strasbourg-Cedex FRANCE

xvii

KURACHI, Hirohisa, Department of Obstetrics and Gynecology, Osaka University Medical School, Osaka, JAPAN

LIDEREAU, R., Centre Rene Huguenin, 5 rue Gaston Latouche, 92211 St. Cloud, FRANCE

LIOTTA, Lance A., Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Building 10, Room 2A33, Bethesda, Mary­land 20892

LIPPMAN, Marc E., Medical Breast Cancer Section, Medicine Branch, National Cancer Institute, Building 10, Room 12N226, Bethesda, Mary­land 20892 U.S.A.

MARTIN, George R., Laboratory of Developmental Biology and Anomalies, National Institute of Dental Research, Building 30, Room 416, Bethesda, Maryland 20892 U.S.A.

MORISSET, Muriel, INSERM Unit 148, 60, rue de Navacelles, 34100 Mont­pellier, FRANCE

MURPHY, L.c., Department of Physiology, Faculty of Medicine, Univer­sity of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba R3E OW3CANADA

MY AL, Y., Department of Physiology, Faculty of Medicine, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba R3E OW3 CANADA

NICHOLSON, S.L., Cancer Research Unit and Department of Clinical Oncology, University of Newcastle upon Tyne, Royal Victoria In­firmary, Newcastle upon Tyne NE1 4LP, UNITED KINGDOM

NUNEZ, A.M., Institut de Chimie Biologique, Faculte de Medecine, 11, rue Humann, 67085 Strasbourg-Cedex FRANCE

NUSSE, Roel, Division of Molecular Biology, The Netherlands Cancer In­stitute, Plesmanlaan 121, 1066 CX Amsterdam, THE NETHERLANDS

OKA, Takami, Laboratory of Molecular and Cellular Biology, National In­stitute of Diabetes, Digestive and Kidney Diseases, Building 8, Room 304, Bethesda, Maryland 20892 U.S.A.

OKAMOTO, Shigeru, Department of Pathology, Osaka University Medical School, Osaka, JAPAN

PIERCE, Jacalyn H., Molecular Biology Section, Laboratory of Cellular and Molecular Biology, National Cancer Institute, Building 37, Room lE24, Bethesda, Maryland 20892 U.S.A.

PONGLIKITMONGKOL, M., Laboratorie de Genetique Molecular des Eu­caryotes du CNRS, Unite 184, de Biologie Moleculaire et de Genie Genetique de l'INSERM, Institute de Chimie Biologique, Faculte de Medecine, 67085, Strasbourg, Cedex FRANCE

REDMOND, S., Ludwig Institute for Cancer Research, Bern Branch, Insel­spital, CH-301O Bern, SWITZERLAND

REICH, R., Laboratory of Developmental Biology and Anomalies, National Institute of Dental Research, Building 30, Room 414, Bethesda, Mary­land 20892

xviii

REICHMANN, E., Ludwig Institute for Cancer Research, Bern Branch, Inselspital, CH-3010 Bern, SWITZERLAND

RENAUD, R., Service Gynecologique et Obstetrical, H6pital Central, 67091 Strasbourg, FRANCE

RIO, M.e., Institut de Chimie Biologique, Faculte de Medecine, 11, rue Humann, 67085 Strasbourg-Cedex FRANCE

ROBERTS, M., Yale University, Department of Biology, Kline Biology Tower, New Haven, Connecticut 06510

ROCHEFORT, Henri, Unite d'Endocrinologie Cellulaire et Moleculaire, (U 148) INSERM and University of Montpellier, 60, Rue de Navacelles, 34100 Montpellier FRANCE

SALOMON, David S., Laboratory of Tumor Immunology and Biology, Division of Cancer Biology and Diagnosis, National Cancer Institute, National Institutes of Health, Building 10, Room 5B43, Bethesda, Mary­land 20892 U.S.A.

SAURER, S., Ludwig Institute for Cancer Research, Bern Branch, Insel­spital, CH-301O Bern, SWITZERLAND

SCHMITT-NEY, M., Ludwig Institute for Cancer Research, Bern Branch, Inselspital, CH-301O Bern SWITZERLAND

SCHONENBERGER, e., Ludwig Institute for Cancer Research, Bern Branch, Inseispital, CH-301O Bern SWITZERLAND

SHIU, Robert P.C., Department of Physiology, Faculty of Medicine, Uni­versity of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba R3E OW3CANADA

STACK, G., Institut de Chimie Biologique, Faculte de Medecine, 11, rue Humann, 67085 Strasbourg-Cedex FRANCE

ST AMPFER, Martha R., Lawrence Berkeley Laboratory, Building 934, Berkeley Laboratory, Building 934, Berkeley, California 94720 U.S.A.

STRACKE, Mary L., Laboratory of Pathology, National Cancer Institute, Building 10, Room B1B47, Bethesda, Maryland 20892

THOMPSON, E.W., Laboratory of Developmental Biology and Anomalies, National Institute of Dental Research, Building 30, Room 414, Bethesda, Maryland 20892

TSUTSUMI, Osamu, Department of Obstetrics and Gynecology, Faculty of Medicine, Tokyo University, Tokyo JAPAN

TSUYUKI, D., Department of Physiology, Faculty of Medicine, University of Manitoba, 770 Bannatyne Avenue, Winnipeg, Manitoba R3E OW3 CANADA

VIGNON, Francoise, ISERM Unit 148, 60, rue de Navacelles, 34100 Montpellier FRANCE

VONDERHAAR, Barbara K., Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Building 10, Room 5B56, Bethesda, Maryland 20892 U.S.A.