BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE

VOL. 40, No.

JUNE 1 964

PATXIOGENESIS ANI) CONTROLIJ

OF

BREAST

CANCER*

JACOB FURTH
Professor of Pathology, Coltollmbia Unjiversity ('ollee of lPhNsicins and Surgeons; Pathology Laboratories, Francis )elafieldfl ositmal, New Y ork
)irector,

25

25ZDANCER is best conceived of as a disturbance in a com| munity of cells which, under normal circumstances, is

|C

types in which a delicate physiological mechanism a~z5E5E~e552 termed homeostasis keeps order. For years I, as well as others, taught that the cancer cell is autonomous and unrestrained and that the nucleus of the cancer problem resides in this rebellious mutant cell. WVe were correct in supposing that most cancer cells were altered but were wrong in ignoring the existence of host factors to which many cancer cells are responsive, and we were wrong in failing to realize that alteration in the controlling forces also can lead to the formation and progressive growth of tumors. We did not recognize that the basic change toward malignancy can reside in the regulatory

[ticomposed of a specific number of cells of different cell

system." 2
This concept is founded on experimental evidence in animals and on observations in man. In man, events are often subject to several
n * The Aonnual .Scioim'lwveis Lecture' of the Ainetc-ic,-in-latitaL Mtei.dtl 'Medical Association, presentel at The New York Academy of Me(licine, Noveinher 9, 190(2. lhe work in the anithor's laboratory has been suppaioited ibs tile National (Cancer listitote of the National I nstitntes of Health, Bethesda, M\l1.

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J. FURTH
j.

FURTH

interpretations and the possibilities of substantiating observations by experimental proof is limited. Primum non nocere. In animals, proof can be sought two ways, by inducing or aggravating a disease and by preventing or alleviating it. The level of knowledge about mammary cancer that has been attained illustrates how progress is achieved by the cross-fertilization of the two avenues of approach, clinical and laboratory. For the clinician, getting the patient well is the primary objective. The research man, on the other hand, is not especially concerned with a frontal attack to control a disease by trial and error; he confronts the problem from a different perspective, trying to get answers on basic questions as he sees them. In I896, the clinician Beatson, faced with the problem of what to do for his patients with breast cancer, conceived the idea that what stimulates the normal breast may also stimulate cancer. He therefore introduced into the treatment of breast cancer the removal of the ovary which is a pacemaker of the growth and function of the mammary gland.3 This brilliant concept, and its practical application, led to a host of major theoretical contributions on the role of hormones in the initiation and maintenance of many neoplasms, a topic not yet fully explored. Today we conceive of a neoplastic cell as an altered cell which perhaps as often as not retains the basic features of its ancestors. Such cells look and function more or less like their predecessors; they often respond to the same stimulating and restraining forces, though usually to a lesser degree. This quantitative difference results in disorderly growth. A few of these errant cells can be arrested by tilting the balance of the homeostatic forces toward restraint. Many cells can be retarded by this means but some are entirely unresponsive to physiological corrective measures.' The three main cancers for which manipulation of the homeostatic mechanism has been successfully attempted are those of the mammary, prostate, and thyroid glands. The best known homeostatic system is that between the thyroid and the pituitary thyrotropes. Thyroid hormone inhibits pituitary thyrotropes, pituitary thyrotropes stimulate thyroid cells. Deranging the system at various points can produce hyperfunction of either type of cell which, if the stimulation is sustained, may result in the formation of tumorous growth either of
Bull. N. Y. Acad. Med.

PATHOGENESIS AND C'ON rROL OF BREAST CANCER

42 5

thyroid cells or of the pituitary thvrotropes.2 A common disturbance in man is depression of the thyroid function byt goitrogens, causing hypersecretion of thyrotropic hormone, which, in turn, produces thyroid tumors. In the following we shall sketch the basic process and mechanisms leading to the control of mammary tumors. Oophorectonly beyond doubt restrains many mammary tumors of man and experimental animals. The isolation of ovarian hormones soon led to the identification of estrogens as the usual ovarian stimulants. But only recently has it been solidly established that estrogens act mainly by stimulating a special pituitary cell, the nmammniotrope which can stimulate the maiiimary gland even in the absence of the ovaries. Large doses of estrogens inhibit the same mammary tumors which they can stimulate in small doses.4 Although the feedback mechanism connecting the mammary gland with the pituitary is not known, it has been established that androgens are to some extent antagonistic to estrogens. Wlrhen it was found that the adrenal gradually compensates for the al)sence of ovarian hormones resulting from oophorectomy, adrenalectomy for control of breast cancer of women was introduced.5 Finally, recognition that the pituitary controls both adrenal and gonadal functions led to the introduction of hypophysectomily.(. 7 In the meantime, laboratory research imiadc several fundamental contributions. It was found that though the various types of mammary tumors occurring in wd omen are similar to those il nlice and rats, they are not identical in biological behavior. The discovery that rat tumors are highly hormone-responsive gave rise to the belief that "extinction" of mammary tumors is possible.- This upsurge of optimism camiouLflaged the fact that procedures which conmpletelv cure rat imammllilaryr tumors fail to cure human mammary tumors. Mlost mouse mammary tumors differ from rat mammary tumors in that they are highly autonomous and are linked to a virus 10 which appears to be specific to this species. Many tumor virologists believe that a virus plays a major role in the induction of mammary tumors in all species. One leading mouse tumor virologist is a crusader for the idea that women should not nurse their babies because he believes that in wvomen, as in Mice, a virus is the prime cause of breast cancer and that this virus is acqu ircd with the mother's milk.11 While this is a possibility, experimental evidence
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H FRT J. . UT

is better interpreted as indicating that cancer has manv causes and that carcinogenesis can be triggered by various means, of which one might be a virus. No mamnmarv tumor virus has been identified thus far in species other than the mouse. Studies of both the hormone-independent viral mammary tumor of the mouse and the highly hormone-dependent, apparently virus-free mammary tumors of the rat have disclosed interesting phenomena. These studies are not immediately applicable to man but are beacons pointing to conceivable similarities in man which are worthy;, of exploration. Experimental evidence supports observations in man indicating that cancer is not a single disease and that the same type of cancer can be induced by different agents. So far three classes of carcinogens are known: i) viruses, 2) certain chemicals, and 3) radiation. In addition, hereditary factors play a significant role in tumorigenesis. Heredity is an ever-present modifier of host response. It may trigger ineoplastic transformation without carcinogenic insults, though less often than Cohnheim conceived. HWhile it is simple to produce mainnmary tumors in mice and rats by these three types of carcinogens 1 2 (and to prevent or control many mammary tumors), the mammary carcinogens of man are unknown. Hereditary liability and hormones are more likely to be promoters than to be prime instigators. The process of carcinogenesis has several comiponents, among w\vhichl are initiation, which implies irreversible alteration of cells, and pronmotion, a process in which the initial cells are stimulated to proliferate.13 Under appropriate physiologic conditions hormones arc specific regulators of the growth and functioning of cells. However, they can also influence the formation and progressive growth of many cancers. Work in our laboratories led to the conclusion that hormones of the pituitary cell, the mamnnotrope, play a determining role in the formation of mammary tumors by the three classes of carcinogens named and in the growth of many of the induced tumors.12 Small doses of carcinogens, which are incapable of producing mammary tumors alone, readily do so w\lhen the mammary gland is stimulated by the mlaniliotropic hornmoncs. Regression of human mammary tumors following oophorectonmy, adrenalectomy and hypophysectonly has been amply illustrated in publications of numerous investigators. Figure i is a schematic presentation of similar events in experimental animals bearing niamiary tumors
Bull. N. Y. Acad. Med.

PATrHOGE[NESIS ANI) ('()NtTROL OF BREAST CANCER

42 7

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Fig. 1. Results of a representative experiment in which various operative procedures wvere )erforlme(d on naimiiniary tNitmor-bearing rats, and following tnitior regression iaiillmotropic hormones were administered by means of grafts of functional inammotropic cells. (See Ref. 4.)

and also shows proof that regression of miammiary tumor was caused iby elimination of maimmnotropes. Replacement of the latter caused a rapid recurrence of the regressed mammary tumor. Estrogens given to hypophysectonlized animals failed to do so. Figure 2 showvs that mammotropic hormones (i\ ItH) reverse the inhibition of mammary tumor growth in hypophysectomized rats. Analysis of the beneficial effects of hypophxysectomy in the control of mammni-nary tullor in XwomIIenI as wvell as in the rat, shows that this effect is attained by removal of mammotropes. Stalk section is not the same as hypophysectomy in that it does away wvith 1ypotlhalamic inhibitors but does not eliminate the secretion of nmammi-otropins. Theoretical considerations negate its clinical use. The neoplastic change in cells results in the creation of new cells witlh different characteristics. Cancer cells are unlike normal cells in that they fail to respond properly to the normal homeostatic regulators or do not recognize them at all. Accordingly, three types of cancer cells have been recognized: a) hormone-dependent, b) hormone-responsive, and c) autonomous.' Furthermore, the neoplastic alteration is not fixed
Vol. 40, No. 6, June 1964

42

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. nd iumainniiotropic hormiones Fio '-. 2 The effects on mannnary tuniors of estra(liol 17- a ad(hmlinistered by gra fts of fun(ctional imninnuiotropic cells ( Mt'l) Note that MtTi and sniall doses of estrogeni stimnittlated, and hi r-e (loses of estrogen inhihited this tuiIor. (From Kim and others, Ref. 4.)

but is subject to further modificatiois, the more aggressive variant gradually outgyrowing the less aggressive omec.1 In man, nearly all mammarVy tumors that hiavc l)ecl studied are of the second or third type. Rat mammarv tUmors arc of the first or second, and mouse miammary tumors arc of the third type. Although the information obtained from sttudies of mamiliary tumIlors in one species is not immediately transferable to other species, the basic mechanlisms of formation andc growth of mammary tumors appear to be alike in the different species. As to the precise events by -which carcin1ogcles and promoters exert inlflueCnce, mnuch is still to be learned in all species. The niature of hiumani mammary carcinogens is not better understood than that of the mammary carcinogens of the rat. Failure to identify -with certainty virus particles in electron
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PATHOGENESIS AND) CONTROIL OF BREAST CANCFR

429

micrographs of either 11hum1an or rat mammary tumors is notewvorthy but not conclusive. Radiation can produce mnammary tumors in most rats but does so less readily in mice. That the incidence of manmmary tumors in irradiated women is not significantly different from that in nonirradiated women is best documented by the recent Hiroshima statistics. Carcinogenic chemicals are excellent mamimnary carcinogens in the rat. The mammary gland is a secretory and excretory organ. The ease of induction of mammary tumors by chemicals is readily explained by their entrapment in the mammary gland. The higher incidence of tumor in women who did not lactate may possibly be explained by supposing that in stagnating milk the carcinogens xvere trapped in the breast whereas the nursing mother excreted the carcinogens with the milk. The main promoters of human mammary tumor are those agents which stimulate the mammary gland and thereby increase the chance of "capture" or retention of the carcinogenic substances and enhance the sensitivity of the cells to carcinogenic modifications, notably by increasing the number of carcinogen-sensitive mnitotic stages.
SUMMARY AND RECOMMENDATIONS How can recent experimental findings in regard to mammary tumors be utilized in the control of human breast cancer and how can laboratory research shed additional light on the genesis of mammary tumors? There are several possibilities: I. Since tumors vary in hormone responsiveness, it is desirable to devise methods to demonstrate the degree of responsiveness of a given tumor to given hormones. To this end, organ cultures are at present of greatest promise. Short-term in -vitro or in7 vLlivo techniques are also conceivable, notably with the use of tritiatecd thymidine uptake as an index of growth activity. Experimental studies indicate that neoplastic cells can not only acquire resistance to the inhibitors of the ancestral normal cells but can even become stimulated by them.' 2. It is desirable to deprive tumor hosts of all mammary glandstimulating factors as soon as possible after discovery of the tumor. This can be accomplished by either surgical ablation of the respective hormone-producing organ or by endocrine "ablation," e.g. inhibition of mammary gland stimulators. Isolated oophorectomy is inadequate,
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J.

FURI1-I H FURT

for the fulcrum of the control of the mammary gland is the pituitary. 3. If a mammary tumor is fully autonomous, endocrine-specific manipulations are of no help. If a mammary tumor is hormone-responsive, theoretically optimal choice is either combined adreno-oophorectomy or hypophysectomy. The former accomplishes about as much as com11plete 1vpoplhvsectomyNr if n10 functional accessory adrenal is present. 4. Isolated oophorectomy is inadequate because the adrenal is likely to compensate by producing inammotrope-stimulating estrogens. While the beneficial effect of adrenalectomy is well established, the mechanism by which this is attained is not entirely clear. Corticoids, too, have some effect on the mammary gland. Further studies are needed on the mode of action of various sex hormones, adrenal corticoids and pituitary hormones, alone and combined in various doses. 5. Ovarian sterilization by radiation, as currently practiced, is not comparable to oophorectomy because the radiation-induced ovarian atrophy does not lead to destruction of all estrogen-producing cells. Secondary hyperplasia of these cells is a menace. 6. Ablative procedures performed in succession, e.g. adrenalectomy following oophorectomy, as now practiced, increase the hazard, because of the additional time allowed for the emergence of more autonomous, less hormone-responsive variants which were not present at the time of the first successive ablative therapy. 7. Since the best known direct stimulants of the mammary gland are the maminiotropic hormones, assaying their levels during evolution and growth of mammary tumors is desirable. The pituitary cell producing the hormones commonly called "prolactin" has been isolated, but it was found that hormones produced by this cell also have growthpromoting, and even some adrenotropic properties. Clarification of the relation between growth hormone and prolactin is desirable. Isolation and analysis of the pituitary hormones by physical, chemical, and hematological means constitute one of the most fascinating areas of endocrinological research. Such research wvill lead to clarification of the pituitary mosaic and feedback function. Quantitative serologic tests of the pituitary hormones hold promise of solving some of the problems discussed. The labeling of these hormones will help to pinpoint the various cell types of the pituitary. 8. Al\ost human mammary tunmors are somewhat hormone-responsive even though they are autonomous, i.e. removal of niammotropes
Bull. N. Y. Acad. Med.

PATHO(CENESIS AND CONTROL OF BREAST CANCER

4 3 I

inhibits, though it does not arrest their growth. Should niainnmotropes prove to be direct stimulants of mammary tumors through contact with the cells, it may be possible to intensify their action by introducing strong radioactive or cytostatic agents into the hormone molecule without destruction of hormonal specificity. 9. In women with high breast cancer hazard, prophylactic hormonal depression of the pituitary mammotropes might be considered. This calls for intensification of the search for steroids which inhibit mammotropes. In this endeavor, work with experimental hormoneresponsive mammotropic tumors may be helpful. Thus the clinical and laboratory advances bring new vistas in knowledge of mammary gland physiology and pathology and in prophylaxis and control of breast cancer.
REFERENCES
1. Furth, .1. Concept of conditioned and autonomlous neoplasms. Ciba Foundation Symposium on Leukemia Research. London, J. & A. Churchill, Ltd., 1954,

8.

lpP 34-41.
2. Furth, J. Influence of host factors on the growth of neoplastic cells, Cancer Res. 23:21-34, 1963. 3. Beatson, G. T. On the treatment of inoperable cases of carcinoma of the manuna: Suggestions for a new method of treatment, with illustrative cases, Lancet 2:104-107 (July 11), 1896. 4. Kim, U., Furth, J. and Yannopoulos, K. Observations on hormonal control of mnammary cancer. I. Estrogen and mamamotropes, J. Nat. Cancer Inst. 31 :23359, 1963. .5. Huggins, C. and Bergenstal, D. M. Inhibition of human malmmary and prostatic cancers by adrenalectomy, Cancer Res. 12:134-41, 1952. 6. LuIft, R. and others. Hypophysectonmv in the mimanagement of metastatic carcinoma of the breast. In Endocrine Aspects of Breast Cancer. A. R. Currie, ed., Edinburgh, E. & S. Livingstone, Ltd., 1958, pp. 27-85. 7. Ray, B. S. and Pearson, 0. H. Hypop)h1ysectommmy in treatment of a(lvanced
9.

10.
11.

12. 13.

14.

1.5.

cancer of the breast, Ann. Sary. 14;: 394-403, 1956. Ray, B. S. and Pearson, 0. H. IHypophysectomy in treatment of disseminated breast cancer, Sury. Clin. N. Amer. 42: 419-33, 1962. Huggins, C. and Yang, N. C. Induction and extinction of mammnary cancer, Science 1X,7:257-62 (July 27), 1962. Bittner, J. J. Causes and control of miammniary cancer in mice, Harvey Lect. 42?:22-4(i, 1946-1947. Gross, L. Possibility of preventing breast cancer in women. Is artificial feeding of infants justified? N. Y. J. Med. 47:866-67, 1947. Furth, J. Vistas in the etiology and pathogenesis of tumors, Fed. Proc. .20: 865-73, 1961. RouIs, P. and Kidd, J. G. Conditional neoplasrus and subthreshold neoplastic states; study of tar tumors of rabbits, J. E.1p). Med. 73:365-90, 1941. Berenblumi, I. Mechanismi of carcinogenesis; study of the significance of cocarcinogenic action and related phenomuena, Cazcer Res. 1:807-14, 1941. Foulds, L. Experimental study of tumor progression: Review, Cancer Res. 14:

:327-39, 1954.

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