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

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 alíele.The inher
itance of a single copy of this resistance alíeleis 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 alíele,
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
alíeles.Since F, hybrids between the WF and COP rats are
resistant to DMBA induced mammary adenocarcinogenesis,
this suggests that the COP resistance alíelemay be an epistatic
alíelecapable of suppressing the expression of the several
normally codominant susceptibility alíeles.This would be anal
ogous to the ability of the albino alíele,when present as the
homozygous recessive ce alíeles,to suppress the expression of
a series of dominant (e.g., agouti) and recessive (e.g., hooded)
alíelesresponsible 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 alíeleis responsible for the resistance
of the COP mammary epithelial cell to DMBA, then the genotype with
regard to this resistance alíeleshould 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 alíeles(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 F¡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 alíele,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 alíelesare involved in COP mammary
epithelial cell resistance to DMBA, then the genotype with regard to
these resistance alíeleshould be R,R¡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
alíeles(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 alíeleswere 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 alíeles
(i.e., of 16 rats, 1 should have 0 cancers since it would have the COP
R¡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 alíelesare 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 alíelesand thus
there are 64 possible genotypes in the F2 generation. All of the genetic
combinations except for the r¡r,r2r2r3r3genotype would be phenotyp
ically resistant if the alíeleswere 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 alíelesare 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 +
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