effects of a single pituitary isograft on mammary tumorigenesis … · of the eight negative mice,...

Effects of a Single Pituitary Isograft onMammary Tumorigenesis in Mice*

ANNABELG. LIEBELTANDROBERTA. LIEBELT

(Department of Anatomy, Baylor University Collegeof Medicine, Houston, Texas)

SUMMARY

Single pituitary isografts were transplanted either subcutaneously or intraocularlyinto female mice lacking the mammary tumor agent, DBA/2/f and (C57BL XDBA/2/f) FI hybrids, as well as mice with the mammary tumor agent, RIII and(RIII X C57BL) hybrids. All animals bearing a viable graft showed stimulated mammary glands with milk secretion and functioning corpora lutea. Such animals werecapable of breeding and nursing their young. Mammary cancers developed in theagent-free DBA/2/f and (C57BL X DBA/2/f) F! hybrid mice with pituitary grafts.Pregnancy and lactation influenced mammary tumorigenesis in control RIII mice,but the milk secretion induced by a pituitary graft had a variable effect on tumorigenesis. Force-bred RIII females bearing a pituitary isograft developed mammarycancer at the same time as force-bred controls, suggesting a maximum threshold forhormonal stimulation in mammary tumorigenesis. RIII mice with grafts and allowedto nurse showed a later mean survival than did nongrafted mice. The C57BL straincontributes some form of "genetic resistance" to the (RIII X C57BL) FI hybrid as

manifested by a delay in tumor appearance as compared with that in the force-bredRIII parent stock. This delay in time of tumor appearance was overcome by theeffects of a pituitary isograft. The pituitary isografts in all strains showed an increasein size with time, whether transplantation was subcutaneous or intraocular, andappeared histologically similar to chromophobe adenomas. The results of this studyindicate that a single pituitary isograft removed from its hypothalamic influencescan have significant effects on the development of mammary cancers in intact micedepending upon genetic factors, the presence or absence of the mammary tumoragent, and the breeding history.

Transplantation of the adenohypophysis into excessive hormonal stimulation resulting in mam-hypophysectomized animals results in the con- mary tumor development in mice presumablytinual secretion of several of the trophic hormones, free of the mammary tumor agent (MTA). TheseThis functional activity is more pronounced when observations have been recently confirmed (15).the graft is put back into the sella turcica or an It was the purpose of this investigation to studyadjacent site (16). Loeb and Kirtz (22) reported the effects of a single pituitary isograft on thethat subcutaneous grafting of several pituitaries development of mammary tumors in intact micecaused marked development of the mammary in the presence or absence of MTA.glands of mice as well as an increase in theincidence of mammary tumors. More recently, MATERIALS AND METHODSMÃ¼hlbock and Boot (26) found that grafting The mice used were: (a) the low-cancer strainof multiple pituitaries into mice led to prolonged DBA/2/f (deprived of MTA), (b) the high-cancer

strain RIII (with MTA), and (c) F! hybrids (RIII* Presented in part and published in Proc. Am. Assoc. Can- X C57BL) and (C57BL X DBA/2/f). Mice of the

cerResearch,3:37,1959. DBA/2/f strain were obtained from Dr. J. BittnerSupported by U.S. Public Health Serice grant C-4517. jn ^ &nd had ^^ fostered Qn a C3H/{ female

Receivedfor publication August 4,1960. lacking the MTA. Since then, they have been

86

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LIEBELTANDLIEBELTâ€”PituitaryIsografts and Mammary Cancer 87

inbred in this laboratory for 26 generations. RIIImice were received from Dr. H. Andervont in1954 and now are in their fourteenth inbred generation. The C57BL mice were obtained fromDr. Bittner in 1951 and are now in their eighteenthinbred generation. We have never observed a"spontaneous" mammary cancer in the C57BL

mice.All the host mice remained intact, i.e., had their

own pituitaries. Donor pituitaries were graftedto animals of the same genotype or to an FIhybrid having one parent of the same genotypeas the donor. One pituitary was grafted to eachyoung female recipient. All grafts were from maledonors varying in age from 30 to 200 days. DBA/2/f grafts were placed into the axilla of DBA/2/fmice, and C57BL pituitaries were grafted intothe axilla of the (C57BL X DBA/2/f) females.All the RIII and RIII hybrid mice received oneRIII pituitary in the anterior eye chamber, according to a method described by Browning (6, 7).

Mice were then kept as virgins, were allowedto breed and nurse their litters, or were force-bred,in which case litters were removed shortly afterbirth. All mice were allowed to live until thedevelopment of breast cancer or other disease.Autopsies were usually performed when the mammary tumors were approximately 2 cm. in diameter, and particular attention was directed towardestablishing the viability of the pituitary graft.

In the majority of cases tissue sections were taken of mammary tumors, pituitary isografts, mammary glands, ovaries, adrenals, uteri, vaginas,and other organs. Fixation was in either Techniconor 10 per cent neutral buffered formalin, andstaining was with hematoxylin and eosin and/orAlcian blue-periodic acid Schiff method.

RESULTSThe presence of a pituitary isograft in female

mice resulted in profound effects on the mammarygland, ovaries, and estrous cycles of all strainsof mice studied. Mammary glands of virgin animals showed marked growth and developmentaccompanied by milk-secretory activity within40 days after pituitary transplantation (Figs. 1,2).The ovaries of these animals showed multiplecorpora lutea with occasional mature follicles(Fig. 3). Vaginal cycles were, in general, similarto those previously described (26). Animals manifesting these hormonal effects were capable ofbreeding and nursing their young. The cytologyof the pituitary isografts depended on the ageat which the animal was autopsied. Some RIIIanimals developing mammary tumors at an earlyage (5 months) had pituitary Â¡sograftsshowing

the persistence of some acidophils and basophils,but animals autopsied beyond this age, includingthose of other strains, demonstrated no cytologicaldifferential staining in the grafted pituitaries.

Sixteen DBA/2/f female mice received pituitaryisografts at 37-58 days of age and were bredwith C57BL males. Eight of these animals developed mammary tumors at an average age of554 days (range, 364-728 days) (Table 1). Thisis compared to a "spontaneous" incidence of two

of 91 control breeders, which died at 577 and604 days of age. Experimental and control micewere all of the same subline. Earlier control miceof this subline have never had a higher incidenceof mammary cancer, and biologic assays of the

TABLE1INCIDENCEOF MAMMARYCANCERIN DBA/2/f AND

(C57BL X DBA/2/f) F] HYBRID MICE WITH A SINGLEPITUITARYISOGRAFTAND LACKINGTHE MAMMARYTUMORAGENT

StrainDBA/2/f

forced breedercontrolsDBA/2/f

forced breeder withapituitarygraft(C57BLX

DBA/2/f) forced breedercontrols(C57BLX

DBA/2/f) virgin controls(C57BLXDBA/2/0

virginwithapituitary graftIncidence2/918/160/320/213/8*Mean

survivaltime(day,)577

and604554

(364-728)782

(770-807)

* Four of the five animals negative for mammary cancerdied with leukemia at an average age of 590 (497-807) days.

tumors of these mice for the mammary tumoragent have been consistently negative.1 Five ofthese eight tumor-bearing mice had viable graftsconfirmed histologically, two grafts were questionable, and in one mouse no graft was found.Of the eight negative mice, viable pituitary graftswere found in only three of the animals. Themorphology of the two tumors in control DBA/2/fmice was that of adenocarcinoma with squamousmetaplasia (10). The mammary tumors in sixof eight mice with pituitary isografts were papillary cystadenocarcinomas. The seventh tumor wasa small anaplastic lesion, and the eighth tumorwas a well differentiated adenocarcinoma withmilk secretion.

Eight (C57BL X DBA/2/f)Fi hybrids lackingthe mammary tumor agent received one C57BLmale pituitary in the axilla at 60 days of age.The mice were kept as virgins. The subcutaneous

1A. Liebelt, unpublished.



88 Cancer Research Vol. 21, January 1961

grafts were found in seven of eight animals, andthese graft-bearing animals demonstrated markedly stimulated mammary glands with milk-secretory activity. Mammary tumors were found inthree of eight animals at an average age of 782days (Table 1). Of the five remaining negativeanimals, four died with leukemia at an averageage of 590 days. Anterior pituitary grafts havebeen reported to exert a leukemogenic effect instrain A male mice (27). The incidence of mammary tumors in virgin and force-bred (C57BL XDBA/2/f)Fi hybrids was zero in 21 and zero in32, respectively. Leukemia was observed in three

90

80

70

litters. The force-bred females with pituitary iso-grafts had from zero to four litters each, andtwelve of these animals developed tumors (85.7per cent). Control force-bred females had fromtwo to eight litters each and a mammary tumorincidence of 94.2 per cent. The mean survivaltime in both groups was approximately the same(Table 2).

Twenty-six control RIII breeders (allowed tonurse) had zero to nine litters each, and of the60 litters born to these mice only 28 litters hadat least one offspring weaned. The incidence ofmammary cancer was 88.4 per cent, and the mean

UUZ

oz

3Â«

2DO

60

50

40

30

20

IO

O

125o Colony Breeders y^ = 86.8%

A Forced Breeders -|| = 94.2%

X Allowedto Nurse -ff =sa4%

_Lâ€¢VirginsJ I

-if =87.7%

100 200 300 400 500

SURVIVAL IN DAYS

600 700

CHART1.â€”Theinfluence of pregnancy and lactation on the development of mammary cancer in RIII mice

of 21 virgin and seven of 32 force-bred controls.All seven recovered pituitary grafts were enlargedat autopsy (approximately 0.5 X 0.5 cm.). Nocytological differentiation was noted, and thegrafts were very vascular (Fig. 4).

Mice of the RIII strain in this laboratorydevelop a high percentage of mammary tumors,whether they are virgins (87.7 per cent), forcedbreeders (94.2 per cent), or breeders allowed tonurse their litters (88.4 per cent) (Chart 1). Although the incidence is similar for the three groups,pregnancies and lactation influence the development and growth of the tumors. Twenty RIIIfemales were given one male pituitary isograftto the anterior chamber of the eye at an averageage of 52 days. Fourteen of these animals wereforce-bred, and six were allowed to nurse their

survival time was delayed when compared withthat of force-bred breeders (Table 2). These findings are similar to the tumor incidence and meansurvival time for 144 breeders of our breedingcolony.

Only six mice received pituitary isografts andwere allowed to breed and nurse their litters.There were one to six litters per mouse, and ofthe nineteen litters born eleven were nursed toweaning age. All six of these animals developedmammary tumors, but the survival time appearedto be increased as compared with that of controls(Table 2). At autopsy, all the eye grafts wererecovered, and the grafts in most instances completely filled the anterior chamber of the eye(Fig. 5). The histology of the mammary tumorswas variable, and no consistent difference in mor-



LIEBELT AND LIEBELTâ€”Pituitary Isografts and Mammary Cancer 89

phology could be detected in grafted animalsas compared with controls.

In progress at the present time is an experimenton a group of 25 virgin RIII mice which receivedpituitary grafts 8-12 months ago. Only four micehave died with tumors so far, at 281, 311, 321,and 391 days.

The (RIII X C57BL)Fi hybrid females whichreceived one male pituitary graft showed an incidence of mammary cancer of 100 per cent ineither the force-bred (19/19) or virgin (8/8) females (Table 3). All the pituitary grafts wererecovered, and all the grafted hosts had stimulatedmammary glands. The mean survival time of thegrafted groups was similar, 258 days for the force-bred and 253 days for the virgin females. Thisrepresents a marked enhancement of tumorigenesisas compared with force-bred control (RIII XC57BL)Fi hybrids in which the tumor incidencewas also 100 per cent (24/24) but the meansurvival time was 352 days. Still under observationis the group of seventeen virgin controls, in whichonly three have died with mammary tumors at425, 533, and 598 days. The remaining mice areapproximately 840 days of age.

An experiment in progress with (C57BL XRIII)Fi hybrids is reported here mainly withrespect to the fate of the pituitary isografts inthe anterior chamber of the eye. Mammary tumorsappear later in life in this reciprocal cross (whichhave not received MTA from their mothers).The pituitary grafts in the eyes of these old mice

TABLE2INFLUENCEOFASINGLEPITUITARYISOGRAFTON

MAMMARYTUMORIGENESISIN RIII MICE

ExperimentBreeders

allowed to nurselittersForced

breedersBreeders

allowed to nurse, witha pituitarygraftForced

breeders with apituitarygraftIncidence23/2633/356/612/14Mean

survival time(day.)300

(182-522)255

(170-396)352

(299-459)253

(158-303)

not only fill the anterior chamber but enlargeto the point of ulcerating through the cornea(Fig. 6). These "tumors" are extremely vascular

and lack the usual pituitary cytological differentiation.

Mammary tumorigenesis appears to be enhanced in these hybrids also. Two of four force-bred breeders with grafts died with tumors at

297 and 483 days, as compared with one of 43force-bred controls which died of cancer at 803days. Virgins bearing a pituitary in the eye showedan incidence of 8/13, with a mean survival of714 days.

DISCUSSIONThe genesis of spontaneous mammary cancer

in mice is considered to be dependent upon theinteraction of three major factors: (a) genetic

TABLE 3INCIDENCEOFMAMMARYCANCERIN (RIII X C57BL)

F, HYBRIDSWITHPITUITARYISOGRAFTS

ExperimentRIIIXC57BL

forced breedercontrol

RIIIXC57BL forced breederwith a pituitary graft

RIIIXC57BL virgin controlRIIIXC57BL virgin with a pi

tuitary graftIncidence24/2419/193/17*8/8Mean

survival time(day<)352

(240-474)258

(186-316)519(425-598)253

(222-302)

* Fourteen of these animals are still alive at an averageage of 840 days.

susceptibility, (6) hormonal stimulation, and (c)the mammary tumor milk agent (4). The importance of the mammary tumor agent can apparently be superseded by the other two factorsunder certain conditions (2, 18, 19). Miihlbockand Boot (26) induced mammary tumors in femaleanimals of six inbred mouse strains and two hybrids, all without the mammary tumor agent,as a result of prolonged and excessive hormonalstimulation. This was accomplished by the implantation of multiple hypophyses (twenty to 200per recipient), which had both a mammotrophicand luteotrophic effect, on the respective targetorgans.

The present experiment demonstrates that asingle pituitary isograft may "induce" mammarytumors in agent-free mice, DBA/2/f and (C57BLX DBA/2/f)Fi hybrids. Animals bearing a pituitary graft either subcutaneously or in the anteriorchamber of the eye show stimulated mammaryglands with profuse milk secretion and functioningcorpora lutea as manifested by vaginal cyclessimilar to those previously described (26). Itshould be kept in mind that all animals withpituitary grafts had their own pituitary glandintact.

The incidence of mammary tumors is similarin the RIII strain and the (RIII X C57BL)Fihybrid (94 and 100 per cent), but the meansurvival time is significantly prolonged in force-bred FI hybrid females as compared with the



90 Cancer Research Vol. 21, January 1961

RIII parent stock with a similar breeding history.Pituitary isografts had an accelerating effect inthe Fi hybrids so that deaths in this group occurred at an age comparable to that in the RIIIforce-bred controls. At the same time, no acceleration was observed in RIII force-bred animalsbearing pituitary grafts. It would appear that theC57BL parent strain contributes a type of genetic"resistance" to account for the delay in tumorappearance in the FI hybrid, but this "resistance"

may be overcome by the hormonal stimulationafforded by a pituitary graft. Andervont (1) suggested that hybridization may influence the development of mammary tumors by affecting thegenetic factors which determine the degree ofsusceptibility to the MTA or to hormonal stimulior both.

The results of the present experiment also indicate the important role of a maximum thresholdfor hormonal stimulation in mammary tumori-genesis. The stimulating effects of a pituitaryisograft superimposed upon the enhancing effectsof force-breeding did not shorten the mean survivaltime in RIII mice.

Among high breast cancer strains of mice spontaneous tumors occur earlier and in a higher percentage of breeding mice than of virgins (9, 20).Rapid breeding with no nursing (force-breeding)enhances mammary tumorigenesis in the presenceor absence of the milk agent (5, 9). Stated in analternative way, nursing may have an inhibitingeffect on tumor incidence and time of appearance(25). Also, it has been found that lactation following pregnancy or the hormonal state (stimulatedmammary glands) resulting from a pituitary isograft was associated with a decreased growth rateof a transplanted RIII mammary tumor (21).

In view of these background data it was anticipated that the "lactogenic effect" of pituitary

grafts might have an inhibitory or delaying effecton mammary tumorigenesis. However, the survival of RIII forced breeders bearing a pituitarygraft was not delayed in the presence of profusemilk secretion in the mammary glands. Graft-induced milk secretion appeared to complementthe effects of nursing to increase survival time in

the six grafted females allowed to nurse. It mightbe noted that the breeders with isografts nursedeleven of nineteen litters to weanling age as compared with 28 of 60 litters of control breeders.This study is being extended to determine theonset of tumors, comparative growth rate of tumors, and survival in mice bearing pituitary graftswith controls.

MÃ¼hlbockand Boot (26) reported that themorphology of the grafted pituitaries was similarin appearance to the spontaneous tumors of thepituitary in situ, which are usually called "chromo-phobe adenomas." The seven grafts recovered

from the axilla of (C57BL X DBA/2/f)F, hybridswere enlarged at autopsy (approximately 0.5 X0.5 cm.). The intraocular grafts especially in(C57BL X RIII)Fi hybrids often enlarged to thepoint of ulcerating through the cornea. Such enlarged grafts can be successfully transplanted toother animals and continue to have both mam-motrophic and luteotrophic effects (3). Histologi-cally, these transplan table tumors resemble chro-mophobe adenomas, with characteristic large "vascular lakes" and one predominant cell type. Siper-

stein and Greer (28) reported that, after transplantation of newborn pituitaries into the eye,the acidophils were only rarely seen by 51 days,the basophils were rare at 36 days, while thechromophobes were abundant but unlike normal.Similarly, 4-week intraocular transplants into hy-pophysectomized animals were reported (12) tohave an unusually large chromophobe element.The cytological variations of the pituitary grafts of5 months' duration in intact RIII mice is current

ly being investigated.The transplantation of a pituitary gland to

various anatomic sites removed from hypothala-mic influences results in the continued secretionof several of the trophic hormones. Such graftscontinue to produce prolactin (8, 11, 24) as wellas suboptimal levels of adrenocorticotropin (12,23), thyrotropin (13, 14), and somatotropin (17).The importance of hypothalamic-pituitary interrelationships in neuroendocrine mechanisms hasbeen well documented (16).

MÃ¼hlbockand Boot (26) have proposed that

FIG. 1.â€”Mammary gland #4 of an RIII virgin female at 80days of age. X32.

Fio. 2.â€”Mammary gland #4 of an RIII virgin female, 80days of age, which received an intraocular pituitary isograft at35 days of age. X32.

Fio. 3.â€”Ovary of an RIII virgin female bearing an intraocular pituitary graft for approximately 45 days. Note thenumerous corpora lutea. X32.

Fio. 4.â€”Asubcutaneous pituitary isograft in a (C57BL X

DBA/Ã¤/f) F] hybrid approximately 400 days after transplantation. X60.

FIG. 5.â€”Apituitary isograft which completely filled theanterior chamber of the eye of an RIII virgin female approximately 250 days after transplantation. X330.

FIG. 6.â€”Apituitary isograft in the anterior chamber of a(C57BL X RIII) Fi hybrid approximately 700 days after transplantation. Note the ulcÃ©rationof the graft through the cornea.X32.



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LIEBELTANDLIEBELTâ€”PituitaryIsografts and Mammary Cancer 91

the continuous secretion of prolactin by the pituitary grafts is the primary causative factor in thedevelopment of mammary cancer in agent-freemice. The present study supports this hypothesisbut, in addition, indicates that further attemptsto elucidate the hormonal mechanisms as influenced by genetic factors as well as the mammarytumor agent can be conveniently carried out byutilizing a single pituitary graft.2

ACKNOWLEDGMENTS

The encouragement and guidance of the late Dr. ArthurKirschbaum during the initiation of this study is respectfullyacknowledged.

REFERENCES

1. ANDERVONT,H. B. Influence of Hybridization upon theOccurrence of Mammary Tumors in Mice. J. Nat. CancerInst., 3:359-65, 1948.

2. ANDERVONT,H. B., and DUNN,T. B. Response of Mam-mary-Tumor-Agent-free Strain DBA Female Mice to Percutaneous Application of Methylcholanthrene. J. Nat.Cancer Inst., 10:895-925, 1950.

3. BARDIN,C. W., and LIEBELT,A. G. Neoplastic ChangesOccurring in Pituitary Isografts in Mice. Proc. Am. Assoc.Cancer Research, 3:93, I960.

4. BITTNER,J. J. The Causes and Control of Mammary Cancer in Mice. The Harvey Lectures, 42:221-46, 1946-47.

5. . Experimental Aspects of Mammary Cancer inMice. In: E. F. LEWISON(ed.), Chapter IV. Breast Cancerand Its Diagnosis and Treatment, pp. 75-102. Baltimore:Williams & Wilkins, Co., 1955.

6. BROWNING,H. C. Heterologous and Homologous Growthof Transplants during the Course of Development ofSpontaneous Mammary Tumors in C3H Mice. J. Nat.Cancer Inst., 8:173-89, 1948.

7. . The Action of Tumors on Normal Tissue Synchronously Transplanted into the Anterior Chamber ofthe Mouse Eye. Cancer Research, 12:13-18, 1952.

8. DESCLIN,L. A. Hypothalamus et libÃ©rationd'hormone

lutÃ©otrophique.ExpÃ©riencesde greffe hypophysaire chez lerat hypophysectomisÃ©.Action lutÃ©otrophiquede l'oeyto-cine. Ann. endocrinol., 17:586-95, 1956.

9. DMOCHOWSKI,L. The Milk-Agent in the Origin of Mammary Tumors in Mice. Adv. Cancer Research, 1:103-72,1953.

10. DUNN,T. B. Morphology of Mammary Tumors in Mice.In: F. HOMBURGERand W. H. FISHMAN(eds.), The Physio-pathology of Cancer, pp. 123-84. New York: P. B. Hoeber,Inc., 1953.

11. EVERETT,J. W. Luteotrophic Function of Autografts ofthe Rat Hypophysis. Endocrinology, 54:685-90, 1954.

2L. Boot (personal communication) has found single pituitary grafts transplanted to the kidney or spleen to be effectivein inducing mammary cancer in agent-free mice.

12. PORTIER,C., and SELTE,H. Adrenocorticotrophic Effect ofStress after Severance of the Hypothalamo-hypophysealPathways. Am. J. Physiol., 169:433-39, 1949.

13. GREER,M. A. The Role of the Hypothalamus in the Control of Thyroid Function. J. Clin. Endocrinol., 12:1259-68,1952.

14. GREER,M. A.; Scow, R. O.; and GROBSTEIN,C. ThyroidFunction in Hypophysectomized Mice Bearing IntraocularPituitary Implants. Proc. Soc. Exper. Biol. & Med., 82:28-30, 1953.

15. HALBERQ,F.; BITTNER,J. J.; and COLE, H. L. ActivityRhythm and Breast Cancer in Pituitary-isografted C andDg Mice; Effect of Hypothalamus. Proc. Soc. Exper. Biol.& Med., 102:650-54, 1959.

16. HARRIS,G. W. The Neural Control of the Pituitary Gland.Baltimore: Williams & Wilkins, 1955.

17. HERTZ,R. Growth in the Hypophysectomized Rat Sustained by Pituitary Grafts. Endocrinology, 66:926-31,1959.

18. HESTON,W. E. Mammary Tumors in Agent-free Mice.Ann. N.Y. Acad. Sc., 71:931-42, 1958.

19. HESTON,W. E.; DERINGER,M. K.; DUNN, T. B.; andLEVILLAIN,W. D. Factors in the Development of Spontaneous Mammary Gland Tumors in Agent-free StrainC3Hb Mice. J. Nat. Cancer Inst., 10:1139-55, 1950.

20. LATHROP,A. E. C., and LOEB,L. The Influence of Pregnancies on the Incidence of Cancer in Mice. Proc. Soc.Exper. Biol. & Med., 11:38-40, 1913.

21. LIEBELT,R. A. Effects of Lactation and Pituitary Isografts on Mammary Cancer Growth in RIII Mice. Proc.Am. Assoc. Cancer Research, 2:320, 1958.

22. LOEB,L., and KIRTZ,M. M. The Effect of Transplants ofAnterior Lobes of the Hypophysis on the Growth of theMammary Gland and on the Development of MammaryGland Carcinoma in Various Strains of Mice. Am. J. Cancer, 36:56-82, 1939.

23. McDERMOTT,W. V.; FRY, E. G.; BROBECK,J. R.; andLONG,C. N. H. Mechanism 'of Control of Adrenocorticotrophic Hormone. Yale J. Biol. & Med., 23:52-66, 1950.

24. MEITES, J., and HOPKINS,T. F. Induction of Lactationand Mammary Growth by Pituitary Grafts in Intact andHypophysectomized Rats. Proc. Soc. Exper. Biol. &Med.,104:263-66, 1960.

25. MÃœHLBOCK,O. The Hormonal Genesis of Mammary Cancer. Adv. Cancer Research, 4:371-91, 1956.

26. MÃœHLBOCK,O., and BOOT,L. M. Induction of MammaryCancer in Mice without the Mammary Tumor Agent byIsografts of Hypophyses. Cancer Research, 19:402-121959.

27. SILBERBERG,M., and SILBERBERG,R. Malignant Lymph-oid Tumors in Orchidectomized Mice Receiving Hypo-physeal and Ovarian Grafts at Various Ages. Proc. Soc.Exper. Biol. & Med., 72:547-50, 1949.

28. SIPERSTEIN,E. R., and GREER,M. A. Observations on theMorphology and Histochemistry of the Mouse PituitaryImplanted in the Anterior Eye Chamber. J. Nat. CancerInst., 17:569-99, 195fi.



1961;21:86-91. Cancer Res Annabel G. Liebelt and Robert A. Liebelt Tumorigenesis in MiceEffects of a Single Pituitary Isograft on Mammary

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