Download Induction of Mammary Cancer with

Induction of Mammary
II. Histological
Cancer with Methylcholanthrene*
Similarity between Carcinogen-induced
Tumors and Certain Mammary Neoplasms
Occurring Spontaneously
ARTHURKIRSCHBAUM,
PH.D., M.D.
(From the Department of Anatomy, University of Minnesota Medical School, Minneapolis, Minnesota)
The onset of mammary cancer has been accel
erated in female mice of the dba stock by the ad
ministration of carcinogenic hydrocarbons (4, 8,
11). When the milk-agent was excluded by fosternursing or by hybridization (e.g., F! hybrid crosses
between dba males and females of a second stock
lacking the milk-agent), it was still possible to in
duce mammary cancer by administering methylcholanthrene (7, 10). In the low mammary cancer
NHO stock, methylcholanthrene was carcinogenic
for the mammary gland (13).
Carcinogen-induced adenocarcinomas of the
mouse mammary gland are characterized by a
large amount of squamous epithelial metaplasia,
whether the carcinogen is dissolved in benzene and
applied to the skin overlying the mammary gland
(8, 10), injected intravenously (7), administered
intranasally in oil (8), or applied subcutaneously
at sites far removed from the development of
mammary cancer (6). This histologie picture could
be interpreted as a specific result of the keratinizing influence of the carcinogenic hydrocarbon;
keratinized masses are to be found within only 10
per cent of the adenocarcinomas arising spontane
ously in stocks which possess the milk-agent and
exhibit a high incidence of mammary cancer (3).
In a report comparing the histology of spon
taneous and carcinogen-induced mammary cancer
it was concluded that the spontaneous and induced
tumors are dissimilar in both their final structure
and their histogenesis (10). The spontaneous
mammary tumors studied had arisen in mice pos
sessing the milk-agent. Recently the author has
studied mammary tumors arising spontaneously
in hybrid crosses between females of the low mam
mary cancer NH1 strain and males of subline 212,
* This, investigation has been aided by grants from the
Jane Coffin Childs Memorial Fund for Medical Research, the
National Cancer Institute, and the Cancer Fund of the Gradu
ate School of the University of Minnesota.
strain dba. The histologie structure of these tu
mors was found to be similar to that observed in
the carcinogen-induced mammary cancers. This
material is being presented, and its possible sig
nificance is discussed.
MATERIALS AND METHODS
Untreated breeding female mice of the NH
stock were observed for spontaneous mammary
cancer. In approximately 500 females only one
mammary tumor has been seen (Fig. 1). XH mice
TABLE1
OCCURRENCE
OFMAMMARY
TUMORS
INHYBRID
MICEOFTHENH ANDDF)A-(212)
STRAINS
Genetic constitution
NHXD F,*
NHDXNHDF,
NHDX D back-cross
Total or range
* D indicates
No. of
mice
18
15
9.9.
55
No. with
mammary
cancer
3
3
1
Age of
mammary
cancer (months)
30-34
22-30
22-26
22-34
dba-Ã-lÃ-.
were crossed with animals of the dba strain (subline 212), so that the maternal influence was al
ways provided by the NH stock. The groups and
numbers of hybrid mice studied are presented in
Table 1.
Hybrids all were breeding animals and were ob
served for the occurrence of mammary tumors.
Those neoplasms which appeared were studied
histologically. Comparison was made between the
sections of these tumors and of mammary tumors
in our collection (a) arising spontaneously in mice
with the milk-agent, Strong A, dba, and (C3H X
dba) FI hybrids, and (6) induced by methyl
cholanthrene in mice with, e.g., dba-212, and with1NH mice obtained from Dr. L. C. Strong, of Yale I'niversity School of Medicine, in the eighth inbred generation in
1941 and now in the twenty-fifth inbred generation.
93
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-
- *
•
FIGS. I TO 3
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KIRSCHBAUM—Mammary Cancer with Methylcholanthrene.
out the milk-agent, e.g., Zb mice (10) and the
progeny of dba-212 mice fostered by a Zb female.
Methylcholanthrene
was dissolved in l)enzene
(0.25 per cent solution) and was painted on the
skin three times weekly for from eighteen to fifty
times, the site of painting being varied to delay the
development of skin tumors (4).
OBSERVATIONS AND DISCUSSION
The incidence and age of appearance of mam
mary tumors in the hybrid mice are presented in
Table 1. The incidence of mammary tumors was
low. This, together with the late appearance, sug
gests that the milk-agent is not present in the NH
stock.
The typical appearance of these tumors is il
lustrated in Figs. 1 and 2. Histologically they are
indistinguishable
from methylcholanthrene-induced cancers (Fig. 3). The large amount of
squamous metaplasia differentiated them from the
spontaneous mammary adenocarcinomas of high
cancer stocks, in which islands of keratinized
epithelium are found in only a small per cent (9).
Unfortunately, tumors of F! hybrid mice of the
dba X NH cross were not studied histologically.
Such mice would be genetically identical with the
FI hybrids studied here and would also possess the
milk-agent.
Unpublished data from another laboratory also
reveal that, in spontaneous mammary tumors aris
ing in very old hybrid mice without the milkagent, considerable amounts of squamous epithe
lial tissue are present (11). Other observations in
dicate that spontaneous tumors appearing in the
absence of the milk-agent are not necessarily of
this histologie type (12) and may not be essentially
different histologically from tumors associated
with the milk-agent (6).
The microscopic structure of mouse mammary
cancer described and illustrated here (adenocarcinoma with squamous metaplasia) can be corre
lated with etiology other than the milk-agent (in
one case carcinogenic hydrocarbon and in the
other unknown). The carcinogen-induced neo
plasms of the mammary gland of mice resemble
certain spontaneous tumors of this species, but
these are not the spontaneous adenocarcinomas
usually studied and described for mice. They are
tumors not ordinarily seen, since they appear in
very old females of populations in which the
mammary tumor incidence is low, that is, females
without the milk-agent.
FIG. 1.—Mammary tumor arising spontaneously in the
strain XH female. The only mammary cancer which has been
seen in this stock. Large amount of squamous epithelial meta
plasia. Mag. X70.
FIG. 2.—Mammary tumor arising in an Fi hybrid female
(NHXdba). Both squamous epithelial tissue and epithelium
II
95
Studies are in progress (in collaboration with
Dr. John Bittner) to ascertain whether a mam
mary tumor-inciting agent can be extracted from
these tumors characterized histologically by
squamous metaplasia.
SUMMARY
Spontaneous mammary adenocarcinomas in hy
brid mice of certain genetic constitution, and pre
sumably without the milk-agent, exhibited a pro
nounced degree of squamous metaplasia. The
structure of these tumors was similar to that seen
regularly in methylcholanthrene-induced
mam
mary cancers. It is suggested that this histologie
type of mammary tumor may be indicative of de
velopment independent of the milk-agent.
REFERENCES
1. ANDERVONT,
H. B., and DUNN,T. B. Mammary Tumors
in Mice Presumably Free of the Milk Agent. J. Nat.
Cancer Inst., 8:227-233, 1948.
2. BITTXER, J. J. Inciting Influences in the Etiology of
Mammary Cancer in Mice. Am. A. Adv. Sc. Res. Conf.
Cancer. 1945, pp. 63-96.
3. DUNN,T. B. Morphology and Histogenesis of Mammary
Tumors: A Symposium on Mammary Tumors in Mice, pp
13-38. Am. A. Adv. Sc., 1945.
4. ENGELBRETH-HOLM,
J. Acceleration of the Development
of Mammary Carcinoma in Mice by Methylcholanthrene.
Cancer Research, 1:109-112, 1941.
5. GARDNER,W. U. Personal communication, 1945.
6. HESTON,W. I". Personal communication. Presentation at
meeting of American Association for Cancer Research.
1948.
7. KIRSCHBAUM,
A. Unpublished observations.
8. KIRSCHBAUM,
A., LAWRASON,
F. D., KAPLAN,H. S., and
BITTNER,J. J. Influence of Breeding on Induction of
Mammary Cancer with Methylcholanthrene in Strain dba
Female Mice. Proc. Soc. Exper. Biol. & Med., 56:141-142,
1944.
9. KIRSCHBAUM,
A., and STRONG,L. C. Influence of Carcino
gens on the Age Incidence of Leukemia in the High
Leukemia F Strain of Mice. Cancer Research, 2:841-845,
1942.
10. KIRSCHBAUM,
A., WILLIAMS,W. L., and BITTNER,J. J.
Induction of Mammary Cancer with Methylcholanthrene.
I. Histogenesis of the Induced Neoplasm. Cancer Research,
6:354-362, 1946.
11. MIDER, G. B., and MORTON,J. J. Effect of Methylcho
lanthrene on Intent Period of Breast Tumors in Dilute
Brown Mice. Proc. Soc. Exper. Biol. & Med., 42:583-584,
1939.
12. ORR, J. W. Mammary Carcinoma in Mice Following the
Intranasal Administration of Methylcholanthrene. J. Path.
& Bact., 55:483-488, 1943.
13. STRONG,L. C., and WILLIAMS,W. L. A Genetic Analysis
of the Induction of Tumors by Methylcholanthrene. III.
Local and Remote Induction of Carcinoma of the Mam
mary Gland. Cancer Research, 1:886-890, 1941.
exhibiting the acinar arrangement of mammary adenocarcinoma present. Mag. X150.
FIG. 3.—Mammary tumor induced with methylcholanthrene in a Zb female (C3H lacking the milk-agent). Histo
logically, carcinogen-induced tumors are identical with
mammary tumors arising spontaneously in females without
the milk-agent. Mag. X70.
Downloaded from cancerres.aacrjournals.org on August 9, 2017. © 1949 American Association for Cancer Research.
Induction of Mammary Cancer with Methylcholanthrene: II.
Histological similarity between carcinogen-induced tumors and
certain mammary neoplasms occurring spontaneously
Cancer Res 1949;9:93-95.
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