Vaginal Sensitivity to Estrogen As Related to Mammary Tumor Incidence in Mice J.J

Vaginal Sensitivity to Estrogen as Related to Mammary Tumor Incidence in Mice J.J. TRENTIN,PH.D.*

(From the Department of Anatomy, Yale Unirersity School of Medicine, New Hauen, Connecticut)

The demonstration of the importance of ovarian to estrogen bears no relation to the maternal ex- secretion or exogenous estrogen to a high mam trachromosomal factor. mary tumor incidence in mice was followed by MÃ¼hlbock(2,3), from the same laboratory, con numerous studies of the estrous cycles of mice of firmed the higher estrogen requirement (5-7 times different strains, in an attempt to correlate high as much) of the high tumor dba strain as compared mammary tumor incidence with some peculiarity to the low tumor C57 and 020 strains for a com of the cycle. In general, no significant and consist parable degree of vaginal stimulation by either in- ent correlation could be demonstrated in this travaginal or subcutaneous administration of regard. Korteweg and co-workers, however, fo estrogen. cused attention on the possibility that, whereas Sliimkin and Andervont (4) also reported on the outward manifestations of the cycle might be rela vaginal estrogen-sensitivity of three strains of mice tively constant, fundamental differences may exist of known mammary tumor incidenceâ€”the C57, in the sensitivity of the genital tissues to estrogen, C, and C3H strains. Again the high tumor strain and that such differences may be related to the was more resistant, the C3H strain requiring twice mammary tumor incidence. Van Gulik and Korte as much estrogen as the low tumor C57 and C, weg (5) reported that of one high tumor and two strains for a positive response in 50 per cent of the low tumor inbred strains, compared with regard to mice. It was also reported that, whereas foster vaginal estrogen-sensitivity, the high tumor dba nursing of the high tumor strain by a low tumor strain was the most resistant to exogenous estrogen strain, or vice versa, altered the mammary tumor stimulus, requiring roughly 3 times the amount of incidence, it did not alter vaginal sensitivity to estrogen needed by the low tumor â‚¬¿57strainfor estrogen. a comparable degree of vaginal stimulation. They The present investigation was undertaken to pointed out also that Bonser (1) observed a some determine whether the reported inverse relation what higher percentage of positive vaginal smears ship of vaginal estrogen-sensitivity and mammary in a low mammary tumor strain than in a high tumor incidence is of universal occurrence or mammary tumor strain when both were injected restricted to the few inbred strains of mice studied with equal but varying doses of estrogen. On the thus far. In view of the apparent lack of effect of basis of such findings, they theorized that, since a milk factor on vaginal estrogen-sensitivity, it normal estrous cycle is essential for continued ex would seem improbable that such an inverse rela istence, those strains of low vaginal estrogen-sen tionship could apply to all strains of mice, since sitivity probably produce larger amounts of estro some strains may have a low mammary tumor in gen and that this may be causally related to a high cidence only because of the absence of the milk mammary tumor incidence. They reported also factor. Nevertheless, such an inverse relationship that reciprocal hybrids between the dba and C.57 might conceivably apply when comparison is made strains showed an almost equal vaginal sensitivity only between strains known to possess the milk to estrogen, intermediate between that of the pa factor. rental strains, indicating that vaginal susceptibility MATERIALS AND METHODS Â«Fellowof The Jane Coffin Childs Memorial Fund for Included in the present study are mice of three Medical Research. This investigation has been aided by a grant strains of high mammary tumor incidence, the from The Jane Coffin Childs Memorial Fund for Medical Re C3H, CBA, and A strains, and three of low tumor search. incidence, the C57, JK, and \ strains. In addition, Received for publication June 9. 1950. mice of two high tumor strains free of milk factor 580

as a result of foster nursing are included. These are with the reservation that it may possess a post- the C3H and A strains, designated, respectively, castration extra-ovarian source of estrogen, in the BL and AL. Also studied were three groups of Fl absence of which responsiveness to exogenous hybrids, the CCI (C57 9 X CBA

Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1950 American Association for Cancer Research. 582 Cancer Research strain. This proved to be the most sensitive of the versely proportional, to vaginal estrogen-sensi several strains tested. tivity. Even this relationship does not apply if one If one considers only those inbred strains known also considers the fact that the C57 strain, after to possess milk factor, the C3H, CBA, and A exposure to the milk factor, generally shows a rela strains, the mammary tumor incidence of these tively low incidence of mammary tumors, while strains is directly proportional, rather than in vaginal estrogen-sensitivity remains unaltered TABLE2 PERCENTAGEOFPOSITIVEVAGINALSMEAHSOBTAINEDFROMMICEOFDIFFERENTSTRAINS TREATEDWITHGRADEDDOSESOFESTROGEN

MlCROGRAMB STRAINor HYBRIDGROUP OP ESTRADICI* C'57 .IK C3H BL CCI CC* CBA AB4 AL BENZOATE Per cent positive/Number of smears 0.4 95/22 95/22 91/23 95/21 90/21 94/17 89/19 100/18 0.3 100/23 82/22 100/24 100/11 86/22 100/23 87/39 81/21 82/17 89/19 79/19 0.27 56/32 55/38 58/36 0 25 76/21 44/16 42/19 33/18 0 22 76/21 0.20 70/44 79/68 81/32 86/44 76/45 72/58 52/42 29/17 16/19 6/18 0.15 61/44 76/21 60/10 77/44 71/45 51/41 29/21 0.12 38/21 0 10 96/23 59/22 52/46 61/33 64/44 53/47 24/21 19/21 29/17 16/19 5/19 0 08 50/22 8/24 0/11 23/44 22/46 0.06 46/46 23/22 0.05 9/23 0.04 11/46 0/22

TABLE 3 MINIMUMAMOUNTOFESTROGENGIVINGPOSITIVE VAGINALSMEARSINAPPROXIMATELY 50 PER CENTOFTHE MICE Micrograms of Micrograms of estradici estradiol Strain benzoate Strain benzoate C57* 0 06 CBA t 0 15 JK* 0.08 AB2 02 C3Hf 0.1 N* 0 25-0 27 BL 0.08-0 1 At 0.25-0.27 CCI 0.08-0.1 AL 0 27 CC2 0.1 " Low mammary tumor inbred strains, t Ili-'l mammary tumor inbred strains.

FIG. 2.â€”Percentage of positive vaginal smears from mice of the A strain and fostered A strain treated with \ arious levels of estrogen.

(4). In short, no consistent correlation is demon strable between mammary tumor incidence and vaginal sensitivity to estrogen. Mice of the A and AL strains, and of the C3H and BL strains, showed remarkably similar vagi nal response to the different levels of estrogen. The high rumor ifroins presence or absence of milk factor as a result of lumor strami foster nursing did not significantly alter vaginal sensitivity to estrogen. This is in agreement with the findings of Shimkin and Andervont (4). The similarity of these two sets of dose-response curves FIG. 1.â€”Percentage of positive vaginal smears from mice of three high tumor and three low tumor strains treated with is also of interest in view of the many years during various levels of estrogen. which the lines of descent of the fostered and non-

fostered mice of these two stocks have been in Figure 4. The reciprocal hybrids between the separated. high tumor CBA and the low tumor C57 strains The dose-response curves for the three groups show a vaginal sensitivity intermediate between of hybrids used and for the three parental inbred that of the two parental stocks; whether the fe strains from which they were derived are presented male parent was from the high tumor or low tumor strain made very little difference. As mentioned above, similar results have been reported by Van Gulik and Korteweg (5), using reciprocal hybrids between the dba and C57 strains. The AB2 hybrids between the two high tumor strains, CBA and A, also show a vaginal estrogen- sensitivity intermediate between that of the pa rental strains. SUMMARY 1. The inverse relationship between vaginal sensitivity to estrogen and mammary tumor inci dence that has been reported for limited numbers of strains of mice was found not to apply when larger numbers of strains were studied. This was the case when either all strains or only those known FIG. 3.â€”Percentage of positive vaginal smears from mice to possess milk factor were considered. of the C3H and fostered C3H strains treated with various levels of estrogen. 2. The presence or absence of milk factor, ob tained by foster-nursing or by reciprocal crossing of a high and a low tumor strain, did not alter vaginal sensitivity to estrogen. REFERENCES 1. BONSER,G. M. A Comparison of the Normal Oestrous Cycle and of the Response to the Administration of Oestrin in Two Strains of Mice Differing (Â¡reatlyin Incidence of Spontaneous Mammary Cancer. J. Path. & Bact., 41:38- 42, 1935. 2. MÃœHLBOCK,O.On the Susceptibility of Different Inbred Strains of Mice for Oestrone. Acta Brev. Neerl., 16:18-20, 1947. 3. â€”¿â€”¿.TheOestrone-Sensitivity of the Mammary (Â¡land in Female Mice of Various Strains. Ilritl., 16:22-27, 1948. 4. SHIMKIN,M. B., and ANDERVONT,H.B. Effect of Foster Nursing on the Response of Mice to Estrogens. J. Nat. Can cer Inst, 1:599-606, 1941. FIG. 4.â€”Percentage of positive vaginal smears from mice of 5. VANGULIK,P. J., and KORTEWEG,R.Susceptibility to Fol- three hybrid groups and the three parental inbred strains licular Hormone and Disposition to Mammary Cancer in treated with various levels of estrogen. Female Mice. Am. J. Cancer, 38:506-15, 1940.

J. J. Trentin

Cancer Res 1950;10:580-583.

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