Table Of ContentBreast Cancer 2
Advances in Research and Treatment
Experimental Biology
Breast Cancer
Advances in Research and Treatment
Edited by WILLIAM L. McGUIRE, M.D.
Volume 1 • CURRENT APPROACHES TO THERAPY
Volume 2 • EXPERIMENTAL BIOLOGY
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ßreast Cancer 2
Advances in Research and Treatment
Experimental Biology
Edited by
William L. McGuire, M. D.
University of Texas Health Science Center
San Antonio, Texas
Springer Science+Business Media, LLC
Library of Congress cataloging in Publication Data
Main entry under title:
Breast cancer.
Includes bibliographical references and index.
CONTENTS: v. 1. Current approaches to therapy, edited by W. L. McGuire. v. 2.
Experimental biology.
1. Breast-Cancer. [DNLM: 1. Breast neoplasms. 2. Breast neoplasms-Therapy.
WP870 B8245]
RC280.B8B673 T 616.9'94'49 77-23505
ISBN 978-1-4757-4675-4 ISBN 978-1-4757-4673-0 (eBook)
DOI 10.1007/978-1-4757-4673-0
© 1978 Springer Science+Business Media New York
Originally published by Plenum Publishing Corporation in 1798.
Softcover reprint of the hardcover Ist edition 1798
All rights reserved
No part of this book rnay be reproduced, stored in a retrieval system, or transmitted,
in any form or by any means, electronic, mechanical, photocopying, microf!lming,
recording, or otherwise, without written permission from the Publisher
Contributors
Artbur E. Bodgen, Mason Research Institute, Worcester, Massachusetts
David Colcher, National Cancer Institute, National Institutes of Health,
Bethesda, Maryland
William Drohan, National Cancer Institute, National Institutes of
Health, Bethesda, Maryland
Ronald B. Herberman, Labaratory of Immunodiagnosis, National
Cancer Institute, Bethesda, Maryland
Kathryn B. Horwitz, Department of Medicine, University of Texas
Health Science Center at San Antonio, San Antonio, Texas
Donald Kufe, National Cancer Institute, National Institutes of Health,
Bethesda, Maryland
Mare E. Lipprnan, Medicine Branch, Division of Cancer Treatment, Na
tional Cancer Institute, National Institutes of Health, Bethesda, Mary
land
Daniel Medina, Department of Cell Biology, Baylor College of Medicine,
Houston, Texas
William L. McGuire, Department of Medicine, University of Texas
Health Science Center at San Antonio, San Antonio, Texas
C. Kent Osbome, Medicine Branch, Division of Cancer Treatment, Na
tional Cancer Institute, National Institutes of Health, Bethesda, Mary
land; present address: Department of Medicine, University of Texas
Health Science Center at San Antonio, San Antonio, Texas
Jeffrey Rosen, Department of Cell Biology, Baylor College of Medicine,
Houston, Texas
Lewis M. Schiffer, Cancer Biology Section, Cancer Research Unit, Clini
cal Radiation Therapy Research Center, Allegheny General Hospital,
Pittsburgh, Pennsylvania
V
vi Contributors
}effrey Schlom, National Cancer Institute, National Institutes of Health,
Bethesda, Maryland
Albert Segaloff, Section on Endocrine Research of the Richard W.
Freeman Research Institute, Alton Ochsner Medical Foundation, New
Orleans, Louisiana
Yoshio A. Teramoto, National Cancer Institute, National Institutes of
Health, Bethesda, Maryland
Preface
Breast cancer continues to be the focus of intense basic and clinical
research. In Valurne 1 of this series we dealt exclusively with topics
concerned with therapy. In the present Valurne 2, we turn our attention
to the experimental biology which is the foundation for our understand
ing of problems concerned with breast cancer etiology, mechanisms of
hormone action, cell kinetics, experimental chemotherapy, and markers
of tumor burden. The contributors to the volume are all noted scholars
who are personally investigating these problems.
The first chapter addresses the question, do hormones cause breast
cancer? Segaloff provides us with a rational up-to-date overview of the
existing data. He concludes that hormones by themselves are not tumor
initiators but rather alter the hast environment so that other carcinogens
are effective. lt is pointed out that the selection of the modeltest system
is critical; one can almost assure any desired result by choosing an ap
propriately biased test system.
The question of the role of viruses in the etiology of human breast
cancer remains unanswered despite elegant studies in mause systems.
Schlom and associates using powerful molecular hybridization tech
niques have shown that 95% of viral nucleic acid sequences are very
similar in several strains of mause mammary tumors that appear very
early, while viral sequences from late-appearing tumors in the same
strain may be substantially different. They also show that some viral
sequences are not transmitted via the germ line but may be passed by
the placenta, milk, or seminal fluids. Type-specific and group-specific
immunochemical reactivities can be shown to differ between tumor
viruses from different tumor strains. Although candidate viruses have
been identified from human breast tumors, the authors pointout that
even if viruses are eventually found to be necessary in the genesis of
vii
viii Preface
human breast cancer, they are probably not sufficient in themselves to
cause the disease.
Turning to preneoplastic lesions, the mammary gland offers one of
the few systems where defined preneoplastic lesions can be studied
during progression to neoplasia. Medina has used the mouse mammary
gland for such studies. This model depends on the important point that
mouse mammary tumorigenesis is characterized by the presence of a
precursor stage, the hyperplastic alveolar nodule, which has a greater
probability of developing into mammary carcinoma than does normal
epithelial tissue. A variety of etiologic agents, viral, chemical, and physi
cal, can interact at both the normal and preneoplastic stages to induce
and promote tumorigenesis. This fact may be particularly important
since Medina points out that many of the chemotherapeutic agents
commonly used in human breast cancer therapy are among those com
pounds which can enhance the rate of tumor formation from precursor
lesions. With regard to effects of known carcinogens on precursor le
sions, Medina proposes that precursor lesions are a mixed population of
normal cells, unaltered precursor cells, and carcinogen-altered precursor
cells which are regulated by cell-cell interactions. Carcinogens may
either act directly on precursor cells to alter them and increase their
tumorigenicity and/or indirectly by disrupting the microenvironment
and consequently disrupting normal cell-precursor cell interaction. The
result in either case would be an increased probability of expression of
potentially tumorigenic precursor cells.
Model systems to study the effects of hormones on breast tumor
growth and regression have been available for many years, but have
been fraught with difficulties because of complex interactions between
the various endocrine glands, normal tissues, and the tumor cells. Now
with the availability of a human breast cancer cellline in long-term tissue
culture many of the above problems can be entirely avoided. Osborne
and Lippman use this to show unequivocally the direct effects of estro
gens and antiestrogens on breast tumor cells. They show that androgen,
glucocorticoid, progesterone, insulin, etc. can be studied in a similar
manner. Their approach probably represents the best currently available
model for studying hormone actioninhuman breast cancer cells. Clearly
it has been the stimulus for a number of other laboratories to use these
tissue culture cell lines in unravelling the mechanisms of hormone ac
tion.
Antiestrogens represent a relatively new approach to the treatment
of breast cancer. Horwitz and McGuire review the current state of
knowledge regarding what is known about these remarkable com
pounds. They are clearly as effective in producing objective breast tumor
Preface ix
regressions as any other form of endocrine therapy. Within the tumor
cell they bind to and translocate the estrogen receptor to nuclear sites
and somehow prevent endogenaus estrogens from stimulating tumor
growth; they have several other possible sites of action such as the
pituitary and ovaries as weil. There are certain features of these com
pounds which demand further investigation. For example, it has been
shown that certain doses of antiestrogens can directly stimulate proges
terone receptor synthesis, a property thought previously to be exclu
sively restricted to active estrogens. lt is likely that these compounds will
replace most current forms of endocrine therapy because of their low
associated morbidity, and they will no doubt also play an important role
in adjuvant therapy of primary breast cancer.
The search for biological markers of the presence of breast tumor
cells continues. Heberman suggests that there are several promising
leads for the application of immunologic or biochemical tests to the
diagnosis and management of breast cancer. They include CEA, ferritin,
calcitonin, breast-cyst fluid protein, and urinary hydroxyproline. To
these might be added some measures of immune function and reactiv
ity, particularly lymphocyte counts and subpopulations of rosette
forming cells, lymphocyte-proliferative responses, and leukocyte
migration inhibition. Most of the techniques which are currently being
used need tobe refined considerably. Most studies reported to date have
concentrated on demonstrating differences between populations of
women with breast cancer and control populations; more of the markers
now need to be thoroughly evaluated for their practical use in staging
and monitaring of patients. Procedures still need to be developed for
application to the problems of individual patients.
A great deal of new information is available regarding cell kinetics in
experimental breast cancer. Schifferreviews this subject and provides us
with the following generalizations. Transplantahle tumors are more
highly proliferative than their spontaneaus counterparts and this dif
ference is exaggerated with increasing transplant generations. Metastases
also appear tobe more highly proliferative than their primary tumors. In
general, small tumors are more highly proliferative than large ones, and
tumors near blood vessels appear to be more proliferative than those
further away. However, we cannot extrapolate cell kinetic data from one
experimental breast-tumor system to another because the variability is
very wide even within a single system. Schifferpoints out that clinicians
may have thought that a standard chemotherapy regimen based on
average cell kinetic data could be designed for groups of patients, while
in fact, in view of the variability of the data from one tumor to the next,
the possibility of one overall treatment scheme seems to have little
