THE FUNCTIONAL ACTIVITY OF THE MAMMARY GLAND O F
T H E RAT I N RELATION T O MAMMARY CARCINOMA1
HALSEY J. BAGG
AND
FLORA HAGOPIAN
(From the Douglas Research Laboratory, Memorial Hospital, New York)
Various experiments have shown the importance of functional activity of
the mammary gland in the production of mammary carcinoma in the lower
animals (1-S), while Adair and Bagg ( 7 ) and Adair (8) have observed a
similar relation between functional activity and mammary cancer in women.
Reproductive over-work and non-suckling result in a marked increase in
the incidence of mammary carcinoma in female mice derived from a strain
normally low in such cancer incidence ( 6 ) . This experimental procedure
continued over an extended period apparently subjects the mammary gland
to a prolonged and vigorous hormonal stimulation, mainly ovarian, coupled
with irritation of the epithelium of the gland due to retained secretions within
the ducts. There is also an early “ aging ” effect upon the breeding females,
so that mammary tumors may arise in animals only four to six months of age.
Bagg and Jacksen (6) recorded preliminary results of an experiment designed to test the effect of reproductive over-work and marked functional
activity in the mammary glands on the formation of mammary neoplasms in
female rats of the Wistar strain. These studies have been continued and are
the subject of the present report. The same procedure was used as in the
work with mice. The animals were bred rapidly, starting at an early age, and
were not allowed to nurse their young.
It is the purpose of this paper (1) to record the incidence of spontaneous
mammary gland tumors in 56 female rats of the test group and in 36 control
females allowed to breed normally and to nurse each litter for approximately
five weeks; ( 2 ) to describe the association of benign with malignant mammary
gland tumors, and also the association of mammary growths with disturbances
in the pituitary and adrenal glands, as well as leiomyomatous changes in the
uterus; ( 3 ) to record preliminary results of an attempt to select families of
rats with a “ high-tumor ” or a ‘‘ low-tumor ” incidence by means of our socalled functional test,” these families to be used in a study of the genetics
of mammary gland cancer in rats.
((
EXPERIMENTAL
RESULTS
Incidence of Mammary Gland Tumors in Rats Subjected to Forced Breeding
and Non-suckling
Fifty-six animals constituted the test group. The distribution of breeding
females according to the number of litters per animal is shown in Chart I.
1 Read before the American Association for Cancer Research, Atlantic City, N. J., May 2, 1938.
This investigation has been aided in part by a grant from The International Cancer Research
Foundation.
175
176
HALSEY J. BAGG AND FLORA HAGOPIAN
The number of litters ranged from one to twenty-five. The distribution is
skewed due to the fact that several females died at a relatively early ageeight months or under. The greatest number of females, 11, is found in the
fifth litter group, with 6 in the tenth and 5 in the fourteenth. As indicated
in Chart I, the females began breeding at an early age and had consecutive
litters in rapid order. No. 70 for instance had twenty-five litters with an
average interval of only thirty-one days between the dates of parturition.
Non-suchling experiment
Female Pat6
m = D e a d at15 monChs &Adonocarctnomo
ofrndrnmdr
1
noted
gland
24"rnonth
f$)Fib~o-idenoma
of @=Ad.norna
of mammary
mammary gland
gland noted d t 26'hmonth
noted d t 26'hmonlh
e
-2
m - Leiomyoma of u t e r u s
m-noled a t 2 7 ' h m o n t h
bl
1
1
3
+
S
b
?
8
II
I2
Li 11ere
CHART1. DISTRIBUTION
OF BREEDING
F E M ~ OF
S THE WISTARSTRAINOF WHITERATS,ACCORDING
TO THE NUMBER
OF IJTTERS PER FEMALE;
INCIDENCE OB MAMMARY
TUMORS
In order to simplify this chart, only one type of mammary tumor per female is indicated.
Three animals with uterine tumors are here indicated. For further details see text.
The mammary tumors occurring in this group of females include two
adenocarcinomas, one papillary adenocarcinoma, and one alveolar acinar
carcinoma. One of the cancers was associated with an adenoma of the mammary gland elsewhere in the body. In addition 8 females had fibro-adenomas
of the mammary gland and in 4 the tumors were associated with adenomas of
the same gland. Six additional females developed adenomas which were not
associated with other mammary growths. Four females developed leiomyoma
of the uterus and in one of these there was also a fibro-adenoma of the mammary gland.
Adenocarcinoma of the Mammary Gland: The individual records of the
4 females with mammary carcinoma are as follows:
Female N o . 28: Born Aug. 15, 1935; 4 young born Dec. 3; 5 young born Dec. 26; 4
young born Jan. 20; 4 young born Feb. 19; 7 young born April 7; 4 young born May 5 ;
tumor, 2 2 X 20 X 1 2 mm., of left anterior mammary gland noted Feb. 23, when female was
20 months old, Operative removal showed hypertrophic mammary gland with areas of
marked fibrosis (Fig. 1). Local recurrence, removed April 22, showed adenocarcinoma,
malignant (Fig. 2). Death Sept. 1, 1937. Autopsy: No metastases noted, lungs pneumonic,
adrenals large and cystic.
Female N o , 25: Born May 10, 1935; 7 young born Sept. 2; 12 young born Sept. 24;
5 young born Oct. 18; abortion Nov. 7; 6 young born Dec. 5; 5 young born Dec. 29; 4
young born Jan. 21; 6 young born March 16; 4 young born April 13; 6 young born May 18.
On Oct. 13, at 29 months of age, a tumor, 20 X 15 X 3 mm., was removed from the right
anterior mammary gland. Tumor showed marked distention of lobules and ducts by
FUNCTIONAL ACTIVITY OF MAMMARY GLAND OF RAT
177
FIG. 1. RAT 28: SECTION
OF HYPERTROPHIC
MAMMARY
GLANDSHOWINGAREAS OF MARKED
FIBROSIS
OF THE MAMMARY
GL~ND:LOCALRECURRENCE
OF TUMOR
IN
FIG. 2. RAT 28: ADENOCARCINOMA
FIG. 1
FIG.3. RAT2 5 : PAPILLARY
ADENOCARCINOMA
OF THE MAMMARY
GLANDWITH MARKEDDISTENTION
OF LOBULES
AND DUCTS. NOTEADENOCARCINOMA
IN UPPERLEFT AND AT LOWER
RIGHT
FIG.4. RAT25: HIGH-POWER MAGNIFICATION
OF CARCINOMA SHOWN I N FIG. 3
colostrom, necrosis of epithelium, and papillary adenocarcinoma in minute and large areas
(Figs. 3 and 4). Female ill, killed Oct. 19, 1937. Autopsy: Pronounced mammary gland
hypertrophy, lactation with cysts of the mammary gland, no metastases, true adenoma of the
pituitary gland approaching carcinoma in character (see Fig. 5 for microscopic structure and
Fig. 6 for a sagittal section of the brain showing the enlarged pituitary in comparison with
a control), a small pyloric ulcer of the stomach, vagina widely distended, and pelvic symphysis flexed.
178
FIG. 5.
FIG. 6.
HALSEY J. BAGG A N D FLORA HAGOPIAN
RAT
25: ADENOMA
OF
CONTROL BRAINAND
THE PITUITARY
GLANDAPPROACHING
CARCINOMA IN
CRARACTER
BRAINOF RAT25
C U T IN SAGITTAL SECTION, SHOWING THE ENLARGED
PITUITARY IN THE LATTER
(RIGHT)
Female N o . 45: Born Dec. 7, 1935; 7 young born March 18; 8 young born April 10;
7 young born May 4 ; 9 young born June 1; 9 young born June 29; 8 young born July 21;
5 young born Aug. 14; 9 young born Sept. 5; 2 young born Sept. 29; 6 young born Oct. 2 2 ;
5 young born Dec. 14; 6 young born Jan. 11; 6 young born Feb. 8 ; 7 young born March
8 ; tumor of right anterior mammary gland, 6 X 5 X 4 mm., noted March 29, when female
was 17 months of age; 4 young born April 5. The tumor discovered on March 29 was removed April 2 2 : size 10 X 7 X 5 mm.; soft; lobulated; section showed alveolar acinar
carcinoma (Fig. 7). Autotransplants of tumor made. Female died July 26, 1937. Autopsy: No metastases or autotransplants noted, lungs pneumonic, other organs apparently
normal except for a leiomyoma of the right horn of the uterus, 4 X 2 X 2 mm. (Fig. 8).
Female N o . 55: Born Dec. 9, 1935; 5 young born March 30; 8 young born May 2 ; 3
young born May 26; 9 young born June 2 2 ; 9 young born Aug. 7 ; 4 young born Sept. 1 ;
9 young born Oct. 5 ; 10 young born Nov. 16; 6 young born Jan. 11 ; 9 young born Feb. 8 ;
7 young born March 19; 7 young born April 26; 9 young born June 7; 8 young born
FUNCTIONAL ACTIVITY OF MAMMARY GLAND OF RAT
179
FIG. 7. RAT45: ALVEOLAR
ACINARCARCINOMA
OF THE MAMMARY
GUND
FIG.8. RAT45: LEIOMYOMA
OF THE UTERUS
July 1 2 ; 5 young born Sept. 3 ; 3 young born Oct. 14. Death Nov. 9, 1937. Autopsy:
Ruptured uterus and one full-term fetus, lungs pneumonic, other viscera apparently normal.
Tumor of right anterior mammary gland, 8 X 5 X 2 mm., was found to be an adenocarcinoma, grade I (Fig. 9) ; tumor in left anterior mammary gland, 13 X 10 X 4 mm., was
an adenoma.
Fibro-adenoma of the Mammary Gland: There are 8 females with fibroadenoma of the mammary gland in our test group. The number of litters per
female is 3, 4 , 5 , 11, 14, 14, 16 and 25, respectively. The breeding history is
shown in Chart I, and a brief summary of results for these females, as well as
for six others that developed adenomas of the mammary gland, is given in
Table I.
The first 8 females of Table I developed fibro-adenoma of the mammary
gland at least once in their breeding history. The average time of appearance was at twenty-five months of age. The histories of females No. 37, 23
and 69 are similar in that in each the first mammary gland tumor to be observed was an adenoma. Following partial removal by surgical means each
tumor recurred locally as a fibro-adenoma. The surgical procedure removed
all but a small portion of the base of the tumor. This part was left in the body
in order to determine the character of the later development of the growth.
Operative trauma may have had an effect on subsequent changes. The females had ceased breeding for eleven, fifteen and twenty months, respectively,
before the tumors were evident.
The adenoma in female No. 69 is shown in Fig. 10. Histologic study
shows evidence of residual lactation, although the animal had had her last
litter four months previous to the date of biopsy. She was then twenty-two
months of age. Five months later the growth recurred locally as a fibroadenoma, as shown in Fig. 11. Autopsy revealed a leiomyoma of the uterus
as well, which is shown in Fig. 12.
TABLE
1: Summary of Results for Breeding Female Rats with Fibro-adenoma
and Adenoma of the Mammary Gland
(rnos. = months; r. = right: 1. = left; ant. = anterior: post. = posterior)
-
_
.
[nterval
Jetween
last
Age a t
death No. of
in
litters
female
nonths
NO, of
Mammary gland history
37
26
3
21
23
28
5
21
10
29
11
77
33
26
14
88
46
25
16
112
52
26
4
23
69
27
14
87
70
27
25
150
13
30
5
29
26
34
litter
and
tumor
appearance, in
months
Associated
disturbances
15
Inflammatory polyp
of uterus
20
Pituitary hypertrophic. Fibroma and
fibrous polyp of
uterus. Miliary
fibroma of right
ovary
29
25 mos., adenoma, 1. ant.
26 mos., recurrence a s fibroadenoma
26 mos., fibro-adenoma, r.
ant.
26 mos., adenoma, r. ant.
28 mos., recurrence as fibroadenoma
28 mos., intracanalicular
fibro-adenoma, r. post.
28 mos., marked stasis, I .
ant.
19 mos., fibra-adenoma, r.
post.; recurrences a t 21,
23, 27, 29 mos.
24 mos., adenoma, 1. post.;
recurrence a t 27 mos.
23 mos., fibro-adenoma, I .
post.;recurrenceat 25 mos.
25 mos., fibro-adenoma, r.
post,
25 mos., fibro-adenoma, I.
post.
26 mos., fibro-adenoma r.
ant.
22 mos., adenoma 1. ant.
27 mos., recurrence as fibroadenoma
26 mos., fibro-adenoma, r.
ant.
29 mos., adenoma, I. ant.
23
5
14
26 mos., adenonia, 1. ant.
17
26
14
82
21 mos., adenoma, r. post.:
recurrence a t 26 mos.
24 mos., adenoma, 1. post.;
recurrence a t 26 mos.
26 mos., adenoma, r. ant.
6
47
22
13
88
1
58
24
19
129
15 mos., lactating adenoma,
1. post.
20 mos., adenoma, r. post.;
Pituitary hypertrophic. Adrenals
markedly hypertrophic; right adrenal
cystic
Left adrenal cystic.
Pituitary hypertrophic
Adenoma of hypertrophic pituitary. Pancreas hypertrophic:
adenoma of islands
of Langerhans.
Uterine fibroma
Negative
1
Negative
3
Negative
67
21
10
50
recurrence a t 24 mos.
24 mos., adenoma, 1. ant
21 mos., adenoma, r. post.;
recurrence a t 22 mos.
180
4
Unknown, due to
post-mortem
changes
2
Negative
5
Cystic right ovary
21
Right ovary cystic
4
Leiomyoma of uterus
1
Negative
FUNCTIONAL ACTIVITY OF MAMMARY GLAND OF RAT
181
FIG.9. RAT55: ADENWARC~NOMA
OF THE MAMMARY
GLAND,GRADEI
FIG.10. RAT69: ADENOMA
OF
THE
MAMMARY
GLAND
OF THE MAMMARY
GLAND:LOCALRECURRENCE
OF TUMORIN
FIG. 11. RAT 69: FIBRO-ADENOMA
FIG. 10
OF THE UTERUS
FIG.12. RAT69: LEIOMYOMA
In females No. 37 and 23 spontaneous fibro-adenomas occurred in addition
to the growths described above. Both of the females lived to over two years
of age. Autopsy showed disturbances in the uterus of each animal. In one
there was an inflammatory polyp, in the other a fibroma and a fibrous polyp.
In addition, No. 23 showed a hypertrophic pituitary gland and a miliary
fibroma of the right ovary.
Female No. 5 2 had four litters, after which breeding ceased for twenty-one
182
HALSEY J. BAGG AND FLORA HAGOPIAN
FIG. 13. RAT 13: ENLARGED KIDNEYSAND ADRENALS(LOWER PHOTOGRAPH) COMPARED WITH
SIMILAR ORGANS F R O M A CONTROL OF ABOUTTHE SAME AGEAND WEIGHT (UPPER PHOTOGRAPH)
The scale is shown in centimeters. Sections were cut at approximately maximum diameters.
FIG. 14. RAT 34: ATYPICAL
ADENOMA
OF THE MAMMARY
GLAND
months. At twenty-six months of age the animal died and autopsy disclosed
a single fibro-adenoma of the mammary gland and a cystic right ovary.
Female No. 70 had 25 litters in rapid succession and a total of 150 offspring. At twenty-six months of age, one month after the birth of the last
litter, a fibro-adenoma of the mammary gland was noted.
Females No. 10, 33 and 46 had ceased breeding two, four, and five months,
respectively, when fibro-adenomata of the mammary gland were noted. These
growths, and in No, 10 an adenoma as well, showed a tendency to recur locally
after operative removal. Two spontaneous fibro-adenomas were noted in female No. 33 and one in female No. 46. The latter also had a cystic right
ovary.
Adenoma of the Mammary Gland: The detailed records of the 6 females
in this group are shown in Table I. These animals had 5, 5, 10, 13, 14 and
19 litters, respectively. Females No. 47, 58 and 67 developed adenomas of
the mammary gland one, one, and three months, respectively, after the birth
of their last litter. One was a lactating adenoma and the adenomas in the
other 2 animals recurred locally after operative removal.
The records for females No. 13, 29,and 34 are of interest in that all three
showed pronounced hormonal disturbance.
Female N o . 13 had 29 young in 5 litters. She then failed to breed for twenty-three
months and a t twenty-nine months of age an adenoma of the mammary gland was noted.
The animal lived to thirty months and was next to the oldest in our entire group. Autopsy
showed hypertrophy of the pituitary gland and both adrenals were very large with &nomatous hyperplasia of the cortex. Fig. 13 shows the adrenals and kidneys of this animal,
FUNCTIONAL ACTIVITY OF MAMMARY GLAND OF RAT
183
and for comparison similar organs from a control of about the same age and size. The
organs were cut through approximately maximum diameters.
Female No. 29 had 14 young in 5 litters and then ceased breeding for seventeen months
until her death at twenty-six months of age. Autopsy revealed an adenoma of the mammary
gland, a cyst of the left adrenal gland, and a hypertrophic pituitary gland.
Female No. 34 gave birth to a total of 82 young in 14 litters. The litters were born in
rapid succession. The animal then ceased breeding for six months and at twenty-one months
of age an atypical adenoma of the mammary gland was removed from the right posterior
region as shown in Fig. 14. This growth recurred locally five months later. At twenty-four
months of age a similar adenoma was removed from the left posterior mammary region and
at death, two months later, this growth was found to have returned at the same site. Autopsy revealed a third spontaneous adenoma in the right anterior mammary gland region, an
adenoma of a hypertrophic pituitary gland, an adenoma of the islands of Langerhans of the
pancreas, and a uterine fibroma of the right horn of that organ (Figs. 15, 16, and 17). A
ventral view of this animal is shown in Fig. 18. Most of the viscera are removed and the
mammary tissue is shown on the reflected skin. I n the illustration the various growths are
surrounded by small pieces of paper to aid in distinguishing them from the surrounding
tissues.
Incidence of Leiomyoma of the Uterus in Rats Subjected to Forced Breeding
and Non-suckling
In addition to the 18 females just described, Chart I gives the histories of 3
animals that developed spontaneous leiomyomata of the uterus. These animals had 5 , 10, and 10 litters, respectively. As nothing of special interest was
noted in their mammary gland history, their records were omitted from Table
I, and are briefly summarized here.
Female No. 26 had a total of 33 young in 5 litters. She then ceased breeding for approximately eighteen months. About two months after the last litter a swelling, possibly a
retained fetus, was noted in the right uterine horn. The swelling persisted for the following
fifteen months. I t was then removed surgically and was found to measure 30 X 20 X 16
mm. It was mostly necrotic, but a specimen from its inferior portion proved to be leiomyoma, and this has been transplanted successfully for 3 generations. At autopsy, two
months later, the right adrenal was hypertrophic, the mammary tissue moderately developed,
and the pituitary gland was also hypertrophic.
Female No. 16 had 59 young in 10 litters of rapid breeding. A swelling of the right
horn of the uterus was palpated approximately one month after the birth of the last litter,
and a retained fetus was suspected. The swelling gradually increased in size until the entire right horn of the uterus became the seat of an abscess, which was surgically removed.
The animal died about two months later when twenty months of age. Autopsy revealed a
leiomyoma of the left uterine horn.
Femalc No. 41 had 10 litters in rapid succession and gave birth to a total of 6’1 young.
At seventeen months of age, about five months after the last litter was born, a solid mass,
20 mm. in diameter, was palpated in the right horn of the uterus. The animal died when
twenty-seven months of age and autopsy revealed a firm nodule at the bifurcation of the
uterus. It measured 5 X 5 X 4 mm. and histologically was found to be a leiomyoma.
Control Females Allowed to Breed Normally and to Nurse Each Litter for
A pproximatcly ‘Five Weeks
There are 37 females in this group, and the number of litters suckled
ranges from 1 to 8 per female. The experiment is still in progress. The
reproductive activity of these animals is much slower than in those of the
test group just described. Most of the females are still young and in the
184
HALSEY J. BAGG AND FLORA HAGOPIAN
second and third litter groups, and so far only 9 have died. None of these
animals has yet shown a palpable growth of the mammary tissue except female No. 71C, which developed a small fibro-adenoma at twenty months of
age after suckling 7 litters. This animal is still alive.
Selection of Stock for Genetic Studies
We are using our so-called " functional test " method of forced breeding
and non-suckling in an attempt to distinguish those females whose constitution
is favorable to the formation of mammary gland tumors, and those in which
there is a resistance to this tendency. We have set apart, for breeding, offspring from mothers that bore mammary gland cancer, and likewise offspring
from mothers that, in spite of application of the " functional test " method,
showed no evidence of mammary tumors of any kind. These offspring were
raised by foster breeding. There are 146 animals in our groups reserved for
genetic studies. They have now been carried to the fourth generation. We
have extended our " functional test " method to females of subsequent generations as a further means of continued selection. These experiments are
still in progress and will be reported at a later date.
DISCUSSION
There are four points of interest in the results just described.
( 1 ) The method of forced breeding and the prevention of suckling of the
young has made it possible to detect female rats whose constitution is favorable
to the formation of mammary gland tumors. The Wistar strain from which
these animals were derived has a relatively low incidence of spontaneous mammary gland cancer. In a personal communication Dr. Herbert L. Ratcliffe,
who has examined many rats of the Wistar Institute, has kindly supplied the
following information: Of 600 animals examined, 226 had tumors; 6 were
adenocarcinomata and 3, or 0.5 per cent, were of mammary origin. These
animals were presumably breeding normally.
I n our experimental group of 56 female rats 4, or 7 per cent, developed
mammary carcinoma. This figure is probably lower than it should be, since
2 7 of the animals died under what is apparently the cancer age. The first
mammary tumor of any kind to develop was a fibro-adenoma in a rat eighteen
months of age. When 2 7 animals dying under this age are subtracted from
the group, a mammary cancer incidence of approximately 14 per cent is obtained, which is probably nearer the true figure. Nineteen females out of the
2 7 died before they were one year old. When a similar correction is made,
our test group shows a 2 7 per cent incidence for fibro-adenoma of the mammary gland (8 animals), and 20 per cent incidence for adenoma in the same
organ (6 animals).
Our own control group, composed of 37 females breeding normally and
suckling each litter for approximately five weeks, has not yet given final results. The animals are relatively young and are still breeding. One female,
still alive, developed a small fibro-adenoma of the mammary gland at twenty
months of age. This is the only growth so far noted.
(2) The appearance of the mammary gland tumors in relation to the span
FIG. 15. RAT34: SECTION
O F ADENOMA
IN A HYPEKM~OPHIC
PlTUITARY GL4ND
FIG. 16. RAT 34: PHOTOMICROGRAPH
SHOWING
AT UPPERLEFT SECTIONOF AN ADENOIVIA
OF THE
ISLANDS
OF LANGERHANS
OF THE PANCREAS
OF THE UTERUS
FIG. 17. RAT34: FIBROMA
FIG. 18. RAT34: VENTRAL
VIEWWITH MOSTOF VISCERA
REMOVED
Three tumors of the mammary glands are shown on reflected skin; also an enlarged pituitary and a
fibroma of the right horn of the uterus. Small pieces of paper surround points of interest.
185
186
HALSEY J. BAGG AND FLORA HAGOPIAN
of reproductive activity is of interest, Apparently mammary carcinoma in
rats, under the conditions of our experiment, may make its appearance close
to the end of a period of intense reproductive activity (females No. 55: and
45), or 1 2 or 17 months after the birth of the last litter (females No. 28 and
2 5 ) . A similar condition appears to hold for the time of appearance of fibroadenoma and adenoma of the mammary gland in relation to the span of reproduct ive activity.
In 6 females that had bred rapidly, and were then apparently sterile for
long periods of time, a return of apparently renewed functional activity of the
mammary glands was observed prior to the appearance of mammary tumors.
Though the animals were not pregnant, the mammary glands became well
developed and the presence of milk at the nipples was noted on gentle pressure.
These clinical symptoms were found to be associated with disturbances in the
endocrine system, especially in the pituitary and adrenal glands. The pituitary was markedly increased in size, usually showing diffuse congestion, and
in two instances there was a fully developed adenoma in each pituitary. These
observations are in agreement with the recent report of Wolfe, Bryan and
Wright on the pituitaries of 26 old breeding female rats, 3 of which had small
fibro-adenomata of the mammary gland (9). In three of our experimental
animals the adrenals were markedly hypertrophic as well as cystic.
These endocrine disturbances appeared prominently in 3 females with
adenomas of the mammary gland. One female, with three apparently independent spontaneous mammary gland adenomas, had an adenoma of the
pituitary, an adenoma of the pancreas, and a uterine fibroma.
Our results emphasize the apparent importance of prolonged hormonal
stimulation in relation to the experimental production of mammary carcinoma.
It is interesting to recall that Lacassagne, by producing hormonal stimulation
through repeated injections of folliculin benzoate, obtained adenocarcinoma of
the mammary gland in male mice which normally do not show breast tumors (la).
A feature of general interest has been the association of different types of
mammary growths in the same female, or the apparent change in the histologic character of the tumors after incomplete removal of an original growth.
We thus find fibro-adenoma apparently forming on the, basis of an earlier
adenoma, or an adenocarcinoma may appear in one part of the mammary
tissue &I$ an independent adenoma in a distant portion of the mammary gland
of thq same female.
w e would also emphasize the prominence of duct stasis in the mammary
system of our test animals. The lack of proper drainage, due to the prevention of suckling, brought about a retention of milk, which in turn may have
produced an irritating chemical effect upon the mammary gland epithelium.
(3) xhe presence of leiomyoma of the uterus in our rats subjected to
reproductive over-work and showing mammary growths suggests a common
link between the uterus and the mammary gland. This condition is shown in
one of our animals that had an alveolar acinar carcinoma of the mammary
gland and a leiomyoma of the uterus. Three females, however, that had had
5, 10 and 10 litters, respectively, in rapid succession, developed leiomyomas of
the uterus but showed no apparent abnormalities in the mammary system. In
FUNCTIONAL ACTIVITY O F MAMMARY GLAND OF RAT
187
two of these animals uterine abscesses, due possibly to the attempted absorption of retained fetuses, preceded the appearance of the leiomyomata.
(4) Our results show that it is possible by our “ functional test ” method
of reproductive overwork and non-suckling to detect female rats whose constitution is favorable to the formation of mammary neoplasms. By the same
method certain females appear to have a constitution unfavorable to the
formation of mammary tumors of any kind. By the proper selection of offspring we are attempting to establish a “ high-tumor ” and a (‘low-tumor ”
strain to be used in studies of the inheritance of mammary cancer in the rat.
CONCLUSIONS
(1) Rapid breeding and the prevention of suckling (the so-called functional test of these experiments) has made it possible to detect female rats of
the Wistar strain whose constitution is favorable to the formation of mammary
neoplasms.
( 2 ) In 56 females tested, when a correction is made for those animals that
died under the cancer age, the incidence of spontaneous mammary gland
adenocarcinoma, under the conditions of our experiment, was 4 out of 29, or
about 14 per cent. Under similar conditions fibro-adenoma and adenoma of
the mammary gland occur spontaneously in 2 7 and 20 per cent, respectively.
( 3 ) Adenoma of the pituitary gland, hypertrophic cystic adrenals, and
leiomyoma of the uterus have been noted in female rats that have developed
mammary gland adenocarcinoma under the conditions of our experiment.
Similar pathologic disturbances have occurred in association with fibroadenoma or adenoma of the mammary gland.
(4) The presence of stasis, due to the retention of secretions within the
ducts as a result of non-suckling of the young, is a prominent feature associated
with the mammary gland tumors. In addition to the presence of internal
factors of a hormonal nature, it is possible that the chemical irritation of retained mammary gland secretions may bear a causative relation to the onset
of mammary gland tumors in the female rat.
( 5 ) Leiomyoma of the uterus has appeared in 5 females subjected to
reproductive over-work. The tumor has been transplanted successfully.
Fibro-adenoma and adenoma of the mammary gland have also grown well
on transplantation. The adenocarcinoma has failed to grow, and none of
the original or transplanted growths has been observed to metastasize.
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