Genetic Control of Resistance to Chemically ... - Cancer Research

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GENETIC RESISTANCE TO MAMMARY CANCER connective tissue appears to have a higher susceptibility to fibrosarcomatous transformation, when carcinogen is directly applied to the gland, than mammary connective tissue of other rat strains more susceptible to mammary adenocarcinogenesis than the COP rat (i.e., NSD, WF, F344, ACI). This increased sensitivity of the connective tissue of COP rats is not restricted to the mammary gland, however. For example, i.p. injection of DMBA into COP females resulted in 40% of the animals developing i.p. sarcomas while only 10% of the NSD rats similarly treated developed sarcomas. The connective tissue of the female COP may be inherently more sensitive to malignant transformation than similar tissue in NSD rats; however, there may be alternative reasons for these findings. When 50-day-old female COP or NSD rats are given s.c. injections in the flank of 2.5 mg of DMBA dissolved in an oil emulsion in order to produce a slow release of the carcinogen, >70% of the injected animals, independent of rat strain, develop sarcomas at the site of inoculation (data not shown). These results could mean that the connective tissue cells of the female COP are no more sensitive than the NSD but that when injected i.p. or directly applied to the mammary gland, DMBA might not be removed from these sites as rapidly in the COP as in the NSD female. This possibility is based upon the observation of Muggins and Fukunishi (22) demonstrating that when SD rats are given i.p. injections of DMBA no sarcomas develop. In contrast, if DMBA pellets are placed in the perito neum to maintain contact between DMBA and the connective tissue cells for an extended period of time, then peritoneal tumors of the connective tissue were universally induced. Fur ther support for this possibility is the observation that when female rats of both COP and NSD strains are given s.c. injec tions of MNU which very rapidly decomposes spontaneously [i.e., biological half-life approximately l h (23)], neither strain develops any sarcomas at the site of injection. Regardless of whether the observed differences in the suscep tibility of the connective tissue between COP and NSD females are due to differences in the cells themselves or to differences in clearance rates for the carcinogen in different connective tissues of these strains, there still remains the important obser vation that there is a unique dichotomy of resistance versus susceptibility in the mammary epithelium versus connective tissue in the female COP rat. Genetic breeding analysis dem onstrated that the resistance of the mammary epithelium of the female COP rat to DMBA and MNU is due to the mendelian inheritance of a dominant autosomal genetic alÃele.The inher itance of a single copy of this resistance alÃeleis able to prevent both the DMBA and MNU induced development of mammary adenocarcinomas in F, hybrids produced by cross-breeding COP rats to either of the highly susceptible NSD or WF strains. While resistance of the mammary epithelium of the female COP rat is controlled by a single dominant autosomal alÃele, susceptibility to DMBA induced mammary adenocarcinomas in the highly susceptible WF rats has been demonstrated by Gould (30) to be due to a series of codominant autosomal alÃeles.Since F, hybrids between the WF and COP rats are resistant to DMBA induced mammary adenocarcinogenesis, this suggests that the COP resistance alÃelemay be an epistatic alÃelecapable of suppressing the expression of the several normally codominant susceptibility alÃeles.This would be anal ogous to the ability of the albino alÃele,when present as the homozygous recessive ce alÃeles,to suppress the expression of a series of dominant (e.g., agouti) and recessive (e.g., hooded) alÃelesresponsible for coat color in the rat (31). Studies are presently under way to determine if the genetically controlled resistance of the female COP rat to chemically induced mam mary carcinogenesis is due to an intrinsic resistance of the mammary epithelial cells themselves or to some general host systemic factor (e.g., systemic hormonal environment, etc.) which secondarily induces the mammary epithelial cells to become resistant. ACKNOWLEDGMENTS The studies reported in this paper would not have been possible without the continuous expert assistance of Susan P. Dalrymple. The gifted and enlightened help of Ruth Middleton in the completion of this manuscript is likewise gratefully acknowledged. APPENDIX If a single dominant autosomal alÃeleis responsible for the resistance of the COP mammary epithelial cell to DMBA, then the genotype with regard to this resistance alÃeleshould be RR for the COP and rr for the NSD rat. Thus the female F, rat produced by crossing NSD and COP rats would have the heterozygous Rr genotype. The gametes of these Fi hybrid rats would have 2 possible configurations of alÃeles(i.e., R or r) and thus there are 4 possible genotypes in the F2generation; however, since two of the F2 genotypes are equivalent phenotypically to the FI phenotype (i.e., Rr and rR) there are only 3 possible phenotypes. Thus by mendelian principles, the genotypes of the FÂ¡generation will segre gate into a 1 RR:2Rr.l rr ratio. Since the RR and Rr genotypes should both show the phenotype of resistance if resistance is controlled by a single dominant autosomal alÃele,0.77 mammary adenocarcinoma/rat would be expected in the F2 generation [i.e, of four F2 rats, one rat should have 0 mammary cancers since it has the COP RR genotype, one rat should have 2.48 mammary cancers since it has the NSD rr genotype, and two rats should have 0.3 cancer each since they are of the F, hybrid Rr genotype; 0 + 2.49 + (2 x 0.3 mammary cancers) = 3.08/4 rats = 0.77 mammary adenocarcinoma/rat]. If two codominant autosomal alÃelesare involved in COP mammary epithelial cell resistance to DMBA, then the genotype with regard to these resistance alÃeleshould be R,RÂ¡R2R2 for the COP and r,r, r2r2 for the NSD rat. Thus the female Ft rat produced by crossing NSD and COP rats would have the heterozygous R,rt R2r2 genotype. The gametes of these I-, hybrid rats would have 4 possible combinations of alÃeles(i.e., R,R2, R\r2, rtR2, or r,r2) and thus there are 16 possible genotypes in the F2 generation. All of these genetic combinations except for the NSD rtrt r2r2genotype would be phenotypically resistant if the resistance alÃeleswere codominant and thus only 1 of 16 animals in the 1: generation should be as highly susceptible as the NSD parental line. Thus the F2 generation should develop 0.42 mammary adenocarci noma/rat if the resistance were due to 2 codominant autosomal alÃeles (i.e., of 16 rats, 1 should have 0 cancers since it would have the COP RÂ¡R,R2R2 genotype, one rat should have 2.48 cancers since it would have the NSD rtr} r2r2genotype, and 14 rats should have no more than 0.3 cancer each since they are of the heterozygous genotype; 0 + 2.48 = [14 x 0.3 mammary cancers] = 6.68/16 rats = 0.42 mammary adenocarcinoma/rat. If three codominant autosomal alÃelesare involved, the genotype should be R,R, R2R2 RiR] for the COP and r,r, r2r2 r,r, for the NSD rats. The FI hybrid would thus be R,r, R2r2R}r}and the gametes of the FI hybrid would have 8 possible combinations of the alÃelesand thus there are 64 possible genotypes in the F2 generation. All of the genetic combinations except for the rÂ¡r,r2r2r3r3genotype would be phenotyp ically resistant if the alÃeleswere all codominant and thus only 1 of 64 female rats in the F2 should be as highly sensitive as the NSD parental line. Thus the F2 generation should develop 0.33 mammary adenocar cinoma/rat if 3 codominant autosomal alÃelesare involved (i.e., of 64 rats, 1 should have 0 cancers since it would have the COP RtRi R2R2 R)Ri genotype, 1 rat should have 2.48 cancers since it would have the NSD r,r, r2r2r}r} genotype, and 62 rats should have no more than 0.3 cancer each since they are of the heterozygous genotype; 0 + 2.48 + 3962 Downloaded from cancerres.aacrjournals.org on February 22, 2013 Copyright © 1986 American Association for Cancer Research
[62 x 0.3 mammary cancers] = 21.08/64 rats = 0.33 mammary adenocarcinoma/rat). Similar theoretical calculations can be made for the expected number of mammary adenocarcinomas per rat for the F2 generation following exposure to MNU if one, two, or three dominant autosomal alÃelesare involved using the data in Table 2 concerning the number of mammary cancers per rat induced in the parental lines and in the F, hybrids following MNU exposure. REFERENCES GENETIC RESISTANCE TO MAMMARY CANCER 1. Lindsey, J. R. Historical foundations. In: H. J. Baker, J. R. Lindsey, and S. H. Weisbroth (eds.), The Laboratory Rat, Vol. 1, pp. 2-36. New York: Academic Press, 1979. 2. Davis, R. K . Stevenson, G. T.. and Busch, K. A. Tumor incidence in normal Sprague-Dawley female rats. Cancer Res., 16:194-197, 1956. 3. Thompson, S. W., Huseby, R. A., Fox, M. A., Davis, C. L., and Hunt, R. D. Spontaneous tumors in the Sprague-Dawley rat. J. Nati. Cancer Inst., 27: 1037-1057, 1961. 4. Shellabarger. C. J., Bond, V. P., Aponte, G. E., and Cronkite, E. P. Results of fractionation and protraction of total-body radiation on mammary neopla sia. Cancer Res., 26: 509-513, 1966. 5. McCormick, D., Adamowski, C. B., Picks, A., and Moon, R. C. Lifetime dose-response relationships for mammary tumor induction by a single admin istration of/V-methyl-yV-nitrosourea. Cancer Res., 41: 1690-1694, 1981. 6. Burek, J. D., and Hollander, C. F. Incidence patterns of spontaneous tumors in BN/BI rats. J. Nati. Cancer Inst., 5Â«:99-105, 1977. 7. Jacobs, B. B., and Huseby, R. A. Neoplasms occurring in aged Fischer rats with special reference to testicular, uterine, and thyroid tumors. J. Nati. Cancer Inst., 39: 303-309, 1967. 8. Sass, B., Robstein, L. L., Madison, R., Nims, R. M., Peters, R. L., and Kelloff, G. J. Incidence of spontaneous neoplasms in F344 rats throughout the natural life span. J. Nat. Cancer Inst., 54: 1449-1456, 1975. 9. Mackawa, A., and Odashima, S. Spontaneous tumors in ACI/N rats. J. Nati. Cancer Inst., 55: 1437-1445, 1975. 10. Dunning, W. F., and Curtis, M. R. The respective roles of longevity and genetic specificity in the occurrence of spontaneous tumors in the hybrids between two inbred lines of rats. Cancer Res., 6:61-81, 1946. 11. Symeonidis, A. Tumors induced by 2-acetylaminofluorene in virgin and breeding females of five strains of rats and in their offspring. J. Nati. Cancer Inst., IS: 539-549, 1954. 12. Dunning, W. F., Curtis, M. R., and Madsen, M. E. The induction of neoplasms in five strains of rats with acetylaminofluorene. Cancer Res., "â€¢ 134-140, 1947. 13. Cults, J. H., and Noble, R. L. Estrone-induced mammary tumors in the rat. I. Induction and behavior of tumors. Cancer Res., 24: 1116-1123, 1964. 14. Dunning, W. F., and Curtis, M. R. The incidence of diethylstilbestrol-induced cancer in reciprocal I , hybrids obtained from crosses between rats of inbred 3963 lines that are susceptible and resistant to the induction of mammary cancer by this agent. Cancer Res., 12: 702-706, 1952. 15. Huggins, C., Grand, L. C., and BÃºllanles,F. P. Mammary cancer induced by a single feeding of polynuclear hydrocarbons and its suppression. Nature (Lond.), 189: 204-207, 1961. 16. Van Zwieten, M. J. The Rat as Animal Model in Breast Cancer Research. A Histopathological Study of Radiation and Hormone-induced Rat Mammary Tumors, pp. 65-134, The Hague: Martinus Nijhoff, 1984. 17. Sinha, D., and Dao, T. A direct mechanism of mammary carcinogenesis induced by 7,12-dimethylbenzanthracene. J. Nail. Cancer IHM..53:841-846, 1974. 18. Cullino, P. M., Pettigrew, H. M., and Grantham, F. H. JV-Nitrosomethylurea as a mammary gland carcinogen in rats. J. Nati. Cancer Inst., 54: 401-414, 1975. 19. Thompson, H. J., and Meeker, L. D. Induction of mammary gland carcino mas by the subcutaneous injection of 1-methyl-1-nitrosourea. Cancer Res., 43: 1628-1629, 1983. 20. Isaacs, J. T. Determination of the number of events required for mammary carcinogenesis in the Sprague-Dawley rat. Cancer Res., 45:4827-4832,1985. 21. Dao, T. L., and Sunderland, H. Mammary carcinogenesis by 3-methylcholanthrene. I. Hormonal aspects in tumor induction and growth. J. Nati. Cancer Inst., 23: 567-585, 1959. 22. Huggins, C., and Fukunishi, R. Mammary and peritoneal tumors induced by intraperitoneal administration of 7,12-dimethylbene[ajanthracene in new born and adult rats. Cancer Res., 23: 785-789, 1963. 23. Weisburger, J., and Williams, G. Metabolism of chemical carcinogens. In: F. Becker (ed.), Cancer: A Comprehensive Treatise, Vol. 1, pp. 185-234. New York: Plenum Publishing Corp., 1975. 24. Magee, P. V. and Barries, J. M. Carcinogenic nitroso compounds. Adv. Cancer Res., 10: 163-246, 1967. 25. Grubbs, C., Peckhom, J., and Cuto, K. Mammary carcinogenesis in rats in relation to age at time of Â¿V-nitrosoWV-methylureadministration. J. Nati. Cancer Inst., 70: 209-212, 1983. 26. Sydnor, K. L., Butenandt,
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