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Tumor Biology |
Curriculum in Genetics and Molecular Biology [M. G. B.], Division of Laboratory Animal Medicine [S. L. T.], and Departments of Medicine [D. C. B., V. L. C., B. H. K.] and Pathology [V. G.], University of North Carolina, Chapel Hill, North Carolina 27599
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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24% of women that carry a mutant copy of p53
(Li-Fraumeni syndrome) develop breast cancer (9)
. With the
development of technologies that allow rapid introduction of specific
mutations into the mouse, it became possible to generate mice that
carried germ-line mutations in p53 (10
, 11) . It was
anticipated that these animals would provide a model system to study
the mechanism by which this gene contributes to initiation and
progression of tumor growth. However, although mice that are homozygous
or heterozygous for mutant p53 alleles display a diverse
spectrum of tumors, these tumors are primarily lymphomas, and only a
small number of mammary tumors were observed on examination of both
p53+/- and p53-/-
animals (2%; Refs. 12
and 13
). A number of possible reasons for the lack of mammary tumors in p53-deficient mice have been suggested. For example, the transformation of mammary epithelial cells might depend on the accumulation of numerous mutations or an appropriate mammary gland stimulus in addition to loss of p53 function (14) . In comparison, thymic lymphocytes appear to be very sensitive to loss of individual tumor suppressor genes such as p53, suggesting that only a limited numbers of additional mutations are required for malignant transformation. For this reason, animals deficient in p53 may die of lymphomas before sufficient time has elapsed for accumulation of mutations and transformation of mammary epithelial cells. In the human population, exposure to DNA-damaging agents, such as carcinogens and ionizing radiation, is likely to contribute to the accumulation of such mutations. Consistent with this hypothesis, higher incidences of breast cancer were observed in atomic bomb survivors and in women exposed to high-dose ionizing chest radiation during childhood or puberty (15, 16, 17) .
Numerous studies have shown that ionizing radiation can increase the frequency and decrease the age at which tumors are observed in mice. This observation is apparent in animals carrying mutations in known tumor suppressor genes and even more so in animals deficient in genes shown to have a role in DNA repair and maintenance of chromosome stability. For example, exposure of neonatal p53-/- mice to ionizing radiation markedly decreases the latency to tumor formation. A similar decrease in tumor latency has been observed in irradiated p53+/- animals (18) . This treatment also increased the frequency of malignant lymphomas and decreased the incidence of sarcomas in these animals. In contrast, exposure of p53+/- mice to ionizing radiation did not alter the incidence of mammary tumors, and in fact no mammary tumors were identified on analysis of 33 treated p53+/- animals (18) . These findings indicate that exposure to ionizing radiation can decrease tumor latency and alter the frequency with which specific types of tumors arise in p53-deficient animals. These results also suggest that differential exposure of humans and mice to such DNA-damaging agents alone cannot explain the extremely low incidence of mammary tumors in p53-deficient mice as compared to patients with the Li-Fraumeni syndrome.
An additional explanation for the failure of p53-deficient mice to develop mammary tumors may be the increasingly frequent finding that differences in the genetic background on which a tumor suppressor is studied can dramatically alter the tumor spectrum (13 , 19) . It has been shown that the incidence of teratocarcinomas is elevated in p53-/- mice on the 129/Sv genetic background as compared with p53-/- mice on a mixed C57BL/6-129/Sv background (13) . This suggests that different strains of mice contain sets of alleles that modify the impact of the loss of p53 in a cell type-specific manner.
In this study, we examined the impact of modifier genes alone and in combination with ionizing radiation on the development of mammary tumors in mice. We compare the formation of mammary tumors in p53-deficient mice of mixed genetic background to the development of mammary tumors in DBA/2 and BALB/c congenic p53-deficient animals. In addition, we determined whether ionizing radiation can alter tumor latency or spectrum in these three p53-deficient populations. These studies show that loss of p53 function in combination with exposure to DNA-damaging agents can result in the formation of mammary tumors. They also show that mice that are p53 deficient and exposed to DNA-damaging agents have an incidence of mammary tumors similar to that observed in Li-Fraumeni syndrome.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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exon2–6, on a mixed genetic background
(129/SvEv x C57BL/6) were obtained from The Jackson
Laboratory and backcrossed to both the BALB/cJ and DBA/2J backgrounds
to generate female p53-deficient animals for use in survival
experiments (11)
. Those mice heterozygous for the
p53 mutation, between the ages of 4 and 6 weeks, were
exposed to 5 Gy of whole-body ionizing radiation from a
137Cs source (1.24 Gy/min) and monitored weekly for the
presence of tumors, whereas mice homozygous for the p53
mutation were monitored for the spontaneous generation of tumors. Mice
that developed tumors between 1 and 2 cm, along with moribund mice that
did not display visible growths, were euthanized and necropsied. In
several instances, animals died without appearing moribund. These
animals were also necropsied, but autolysis of the tissue prevent
accurate histopathology. Additionally, animals with tissues displaying
distinctive phenotypes associated with lymphomas were not fixed for
histopathological analysis. All animals were cared for in compliance
with Institutional Animal Care and Use Committee regulations.
Genomic DNA was recovered from tail biopsy and mammary tumors, and
genotypes for the wild-type and mutant p53 alleles were
determined by both PCR amplification and Southern blot analysis. The
wild-type p53 allele was amplified using PCR primers
directed against exon 6 (6.5: 5'-ACAGCGTGGTGGTACCTTAT-3') and exon 7
(X7: 5'-TATACTCAGAGCCGGCCT-3'), whereas the mutant
p53exon2–6 allele was amplified using
primers against neo (neo: 5'-CTATCAGGACATAGCGTTGG-3') and X7
(11)
. Additionally, genomic DNA from tail biopsies was
digested with StuI, electrophoresed in a 0.8% agarose gel,
and transferred to Hybond-N nylon membrane (Amersham, Arlington
Heights, IL). Hybridization was done using a 32P-labeled
probe specific for exons 7–9 of the p53 genomic sequence.
This probe was prepared from murine genomic DNA using the primers
5'-CGGCTCTGAGTATACCACCATC-3' and 5'-CTTTTGCGGGGGAGAGG-3'.
Tumor Analysis/Histopathology.
Tumor samples were surgically removed post-mortem and fixed in 10%
phosphate-buffered neutral formalin at pH 7.0. Specimens were processed
for histology, embedded in paraffin, sectioned at 3 µm, and stained
with H&E. Tumors of nonlymphoid origin were classified both by
observation of anatomical location and by histological examination of
tumor biopsies by a veterinary pathologist.
Statistics.
The Kaplan-Meier test was used to calculate the latency to tumor
formation, and the log-rank test was used for evaluation of
significance. The significance of differences in frequencies between
groups and/or tumor types was evaluated by 
2 analysis.
P < 0.05 was considered significant.
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RESULTS |
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10 p53-/-
mice and p53+/+ mice were generated for study.
Few differences were observed on comparison of consecutive generations,
either in the survival time or the spectrum of tumors that developed in
the mice. To increase the power of the analysis, mice were placed into
two groups for comparison, mice derived after 1–3 generations or 4–6
generations of consecutive breeding to BALB/c or DBA/2. In all studies,
only virgin female mice were included. As described previously,
p53-/- female mice were less prevalent in
litters at weaning than expected because of the development of
anencephaly in female but not male p53-/- embryos. This
decreased survival was also observed in the p53-deficient BALB/c and
DBA/2 populations. Twenty-eight p53-/- and 29
p53+/+ BALB/c and 28
p53-/- DBA/2 and 28 DBA/2 control animals
generated from intercrosses of BX1–BX3 p53+/-
animals were monitored biweekly for the development of tumors and
killed when tumors reached 1 cm or when animals appeared moribund. As
shown in Fig. 1A
, the latency to tumor formation was similar for both BALB/c and DBA/2
BX1–3 p53-/- mice (log-rank test,
2 = 1.407, P = 0.24). By 119 days of age, 50% of the p53-deficient BALB/c animals
had developed tumors and were moribund. In comparison, 50% of the mice
carrying DBA/2 alleles survived for 136 days before developing tumors.
Although there was a trend toward a decreased latency to tumor
formation in the p53-/- BALB/c mice as
compared with the p53-/- DBA/2 mice, this
difference in latency to tumor formation between the two populations
was not statistically significant and did not differ significantly from
the mean survival time of the original p53-deficient mice of mixed
genetic background.
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, 50% of the p53-/- mice
generated from BX4–6 on a DBA/2 background survived for >154 days.
Additionally, a significant difference in survival was observed on
comparison of latency to tumor formation in BALB/c and DBA/2
p53-/- BX4–6 populations (log-rank test,
2 = 7.680, P = 0.006).
None of the wild-type mice included in this study developed tumors.
Tumors that developed in the p53-nullizygous mice were classified both
by observation of anatomical location and histological examination by a
trained pathologist. Previous studies of
p53-/- mice of mixed genetic background report
that 72.5% of the mice die after developing lymphomas, primarily of
thymic origin (20)
. In both the BALB/c and the DBA/2
p53-/- populations, this continued to be the
most common tumor type observed (Table 1)
. Mutant p53 homozygotes on either inbred strain did not show
a significantly altered prevalence of lymphomas, and additional
histological examination of the liver, spleen, and kidney from these
mice did not reveal distinct differences in metastases to other organ
systems.
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;
2 = 11.53; P = 0.0007). This tumor type has also been observed in studies of the
p53-/- of mixed genetic background (12
, 18
, 20) . The increase in the incidence of these tumors might
account, at least in part, for the decreased survival of the BALB/c
mice. Similar to the observation of p53-/-
mice on a mixed genetic background, mammary tumors were not observed in
our p53-/- BALB/c or DBA/2 populations
(20)
.
Impact of the DBA/2 and the BALB/c Genetic Backgrounds on
Health and Survival in Mice Heterozygous for a Null p53
Allele.
We next examined the development of tumors in
p53+/- BALB/c and DBA/2 congenic mice. All
heterozygous animals included in this study were obtained by six
generations of backcrossing of the mutation onto either the BALB/c or
DBA/2 genetic background. The survival of these mice, similar to the
p53+/- mice of mixed genetic background was
significantly extended (Fig. 1B)
as compared with the
animals homozygous for the p53 mutation (18)
.
Of the 15 p53+/- BALB/c mice in this study, 11
continue to be disease free after 300 days. Tumors were observed in all
four animals that have died to date, and the location and gross
morphology of two of the tumors are consistent with the development of
thymic lymphoma, whereas two of the p53+/-
BALB/c tumors were classified as mammary tumors. Of the 10 DBA/2
p53+/- mice examined, only a single mouse has
died to date, and no tumor was observed upon necropsy.
Tumorigenesis in Irradiated BALB/c or DBA/2J p53-deficient Mice.
Consistent with published work (11
, 12
, 18)
, our
observations show that p53-/- mice display a
high incidence of lymphomas. The increased frequency of lymphomas in
these mice might obscure the role of p53 and modifying alleles found in
BALB/c and DBA/2 in mammary tumorigenesis. Although preliminary studies
of p53+/- BALB/c mice suggest that mammary
tumors might be observed more frequently in this strain, the latency in
tumor formation in these populations makes these studies difficult.
Previous studies have shown that exposure of
p53+/- mice to ionizing radiation results in a
decreased latency to tumor formation (18)
. We therefore
wanted to determine the impact of ionizing radiation on tumor
formation, particularly on the development of mammary tumors in
p53+/- BALB/c and DBA/2 mice. Nineteen
p53+/- and 19 p53+/+
BALB/c along with 25 p53+/- and 25
p53+/+ DBA/2 female animals between BX1–3 were
exposed to a single dose of 5 Gy of whole-body ionizing radiation. Mice
were observed biweekly, sacrificed when moribund, and necropsied.
Compared with our previous report of unirradiated
p53+/- mice (20)
, the median age
of tumor incidence and morbidity decreased in both
p53+/- irradiated BALB/c and DBA/2J inbred
strain (BX1–3) from 500 days to 236 and 200 days, respectively (Fig. 1C)
. Twenty-eight p53+/- and 32
p53+/+ BALB/c along with 23
p53+/- and 31 p53+/+
DBA/2 animals ranging between BX4 and BX6 were exposed to a single dose
of 5 Gy of whole-body ionizing radiation and monitored for the
development of tumors. Comparison of tumor latency in these animals
showed an additional decrease in the median age of tumor incidence and
morbidity to 207 in BALB/c and 184 days in DBA/2, respectively (Fig. 1D)
.
The survival of wild-type mice was also reduced. A reduction in life
span after exposure to even low doses of ionizing radiation is
consistent with published reports. Surprisingly, this decrease in
survival was greater in the p53+/+ mice
generated from BX1–3 than that observed from BX4–6 in both BALB/c and
DBA/2 mice. Of the deaths observed in wild-type controls, 8 of the 55
DBA/2 p53+/+ mice died of lymphomas, whereas the
cause of death in 6 of the other mice could not be established.
Examination of 52 irradiated BALB/c p53+/+ mice
revealed that 6 control mice developed tumors and 5 mice displayed no
visible tumors at death (Table 1)
.
Tumors arising from irradiated mice heterozygous and wild-type for
p53 on all genetic backgrounds were classified both by
observation of anatomical location and by histological examination of
tumor biopsies by a trained veterinary pathologist. Previous studies
have shown that the most prevalent tumor arising in irradiated
p53+/- mice of mixed genetic background is
thymic lymphomas, indistinguishable from those observed in the
untreated p53-/- mice. Similar to the
p53+/- mice of mixed genetic background, 82%
of the tumors that developed in the DBA/2
p53+/- population were lymphomas. In
comparison, only 41% of the BALB/c p53+/-
population developed this type of tumor. Surprisingly, and in contrast
to both the DBA/2 and mixed p53+/- irradiated
animals, mammary tumors were almost as frequent as lymphomas in the
BALB/c population (37%). This difference in the incidence of mammary
tumors arising from p53-deficient BALB/c mice from that observed in
either p53+/- animals on the mixed or DBA/2
background was statistically significant (Table 2
; 2 = 11.56; P = 0.0007). The change in the relative frequency of mammary tumors and
lymphomas in BALB/c mice was observed equally in both the Bx1–3 and
the Bx4–6 population.
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DISCUSSION |
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BALB/c mice that are homozygous for the mutant p53 allele display an increased incidence of hemangiosarcomas as compared with both DBA/2 p53-/- mice (0%) and p53-/- mice of mixed genetic background in our colony (6%; Ref. 20 ). Previous studies have also noted the development of these tumors in p53-deficient mice (12 , 18) .
Hemangiosarcomas are among the most rare types of soft tissue sarcomas in humans. They comprise <1% of all sarcomas (21) and are rarely, if ever, found in patients with Li-Fraumeni syndrome. However, a possible role for this tumor suppressor gene in the pathogenesis of hemangiosarcomas was suggested by a study of a cohort of 33 patients diagnosed with this tumor (22) . Mutations in p53 were observed in many of the tumors, although the frequency of observed mutations varied depending largely on the tissue in which the tumor arose (22) . Additionally, indirect evidence supporting a role for this pathway in development of these tumors comes from the observation of increased expression of MDM-2, a gene whose transcription is regulated largely by p53, in human hemangiosarcomas (23) . The failure to observe hemangiosarcomas in p53-/- mice on the DBA/2 background and the high incidence of these tumors in p53-/- BALB/c mice and in p53-/- mice of mixed (129/NIH) background suggest that the formation of these tumors is influenced by modifier alleles. It is possible that the modifier alleles necessary for the formation of these tumors, although present in a number of mouse lines, are infrequent in the human population.
The increase in hemangiosarcomas observed in the BALB/c p53-/- mice is consistent with a slight decrease in the survival of this population when compared with both wild-type and the DBA/2 p53-/- animals. However, this difference in median survival was apparent only on comparison of the BALB/c p53-/- and DBA/2 p53-/- mice generated after at least three generations of backcrossing. Our results suggest that the DBA/2 genetic background carries a modifying allele(s) that can increase survival time of p53-/- mice, but that this modifier allele is likely to be recessive, in linkage disequilibria with the p53 locus, and/or that multiple modifiers rather than a single modifier contribute to this difference.
As expected, exposure to ionizing radiation reduced the life span of both the BALB/c and the DBA/2 wild-type mice. The primary tumor type observed in both populations was thymic lymphoma. Exposure of BALB/c and DBA/2 p53+/- mice to ionizing radiation dramatically decreased their life span. This decrease was similar for both congenic lines and did not differ significantly from that observed in our laboratory as well as by other investigators upon exposure of p53+/- mice of mixed genetic background to ionizing radiation (18) . However, although only 1 (5.3%; Ref. 20 ) of the p53+/- mice on a mixed background and 3 (6.8%) of the DBA/2 mice developed mammary tumors, this tumor type comprised 19 of 51 tumors observed in the BALB/c p53+/- mice (37.3%). A corresponding decrease in the frequency of lymphomas was also observed in this population.
Differences in the susceptibility of mouse strains to mammary tumors have long been recognized. These differences have largely been attributed to the fact that a number of mouse lines carried the MMTV3 and that viral transmission occurred to their offspring through the milk. Although most inbred mouse lines still carry proviral copies of MMTV, in most cases the virus is unable to replicate and is not thought to contribute to the formation of mammary tumors. Although the influences of MMTV in these studies are difficult to ascertain, early studies indicated that DBA/2 mice are particularly susceptible to mammary tumors (24) . A high incidence of mammary tumors has also been reported in BALB/c mice; however, analysis of these tumors revealed that the replication of MMTV is defective in this mouse strain (25) . In addition, a high incidence of mammary tumors is observed in BALB/c mice exposed to chemical carcinogens (26) . These observations suggest that both BALB/c and DBA/2 mice carry modifying alleles that might also lead to an increase in the incidence of mammary tumors in mice carrying mutations in tumor suppressor genes. The increase in the frequency of mammary tumors in the irradiated BALB/c p53+/- population is consistent with this supposition. Of the 51 BALB/c p53+/- tumors arising from animals exposed to ionizing radiation, 19 tumors or 37.3% were classified as mammary tumors. It is also interesting to note that the number of mammary tumors observed in BALB/c p53+/- mice after only 1–3 backcross generations was almost identical to the number observed in the p53+/- mice generated after more than 4 backcross generations. In fact, two of six BX1 generation mice developed mammary tumors, and it would be expected that in these animals only a single copy of the BALB/c alleles would be present. Although the numbers of mice examined at each generation were small, these results suggest that at least some of the modifiers that contribute to the susceptibility of these mice to mammary tumor formation act in a dominant fashion. More surprising perhaps was the lack of an increase in the incidence of mammary tumors in the DBA/2 mice. Only 3 of 44 tumors (6.8%) from irradiated DBA/2 p53+/- animals were classified as mammary tumors. A possible explanation for this difference in the incidence of mammary tumors in DBA mice in previous studies and our findings is that alleles placing mice at risk for MMTV-initiated mammary tumors do not necessarily increase the risk for tumors initiated by other events, such as loss of p53 function and/or exposure to environmental agents.
Initial examination of untreated p53+/- BALB/c
mice suggests that modifier genes present in the BALB/c genetic
background alone are sufficient to increase the incidence of mammary
tumors in p53-deficient mice. Four tumors have been examined to date in
this population, and two of them are mammary tumors. These results are
further supported by the report published during the preparation of the
manuscript (27)
. These investigators reported a high
incidence of mammary tumors in untreated p53+/-
BALB/c mice. Similar to the tumors that we have observed in the
untreated p53+/- BALB/c mice, these tumors
appear late in life; however, the incidence of the mammary tumors is
similar to the incidence in our irradiated
p53+/- BALB/c animals. Additional support for
the presence of modifiers in the BALB/c background that make the
mammary epithelial cells particularly sensitive to malignant
transformation, especially upon loss of p53, comes from transplantation
studies. A high incidence of mammary tumors was observed after
transplantation of p53-/- BALB/c mammary
epithelial cells into the cleared fat pads of isogenic mice as compared
with control studies carried out with wild-type cells
(27)
. Unlike treatment of p53+/-
BALB/c mice with ionizing radiation, the incidence of mammary tumors in
BALB/c recipient mice from these transplantation experiments did not
significantly increase after exposure of these mice to chemical
carcinogens (28)
. This contrasts with the results of our
study in which we have shown that the median latency to mammary tumor
formation is decreased by 6 months in p53+/-
BALB/c mice exposed to ionizing radiation. This may suggest that repair
mechanisms for DNA damage induced by radiation are particularly
sensitive to a deficiency in p53, whereas for the most part, the rate
of repair of chemical-induced lesions is not altered by loss of p53.
A previous report has shown that radiation-induced chromosomal aberrations from BALB/c mammary epithelial cells persisted for up to 28 population doublings, whereas chromosomal aberrations from similarly treated C57BL/6 cells were repaired within six population doublings (29) . This suggests an inherent deficit in the ability of BALB/c epithelial cells to repair specific types of DNA damage, particularly those induced by ionizing radiation. A possible explanation for the decreased repair in the BALB/c cells was suggested by a recent report showing that BALB/c cells have decreased levels and activity of DNA-PKcs protein (30) , an enzyme involved in nonhomologous end-joining and DNA double-strand break repair. An increased incidence of these types of damage would be expected after exposure to radiation. The observation of mammary tumors in p53+/- BALB/c but not in p53+/- DBA/2 mice and the decrease in the latency of tumor formation after exposure to ionizing radiation are consistent with a model in which: (a) accumulation of DNA lesions, such as double-strand breaks, contribute to mammary tumorigenesis; (b) the frequency of these lesions is increased by exposure to ionizing radiation; (c) these lesions accumulate more frequently in BALB/c mice because of deficits in repair pathways; and (d) p53 is important in protecting cells from accumulation of these lesions.
In summary, the development of mammary tumors in p53-deficient mice is influenced by modifier alleles. Alleles present in the BALB/c background increased the incidence of mammary tumors in the absence of normal p53 expression. The latency of tumor formation can be altered in p53-deficient BALB/c mice by exposure to ionizing radiation. In comparison, ionizing radiation decreases the latency to development of lymphomas but not mammary tumors in p53+/- DBA/2 mice. The identification of these genes should contribute significantly to our understanding of factors that put individuals at risk for developing breast cancer. In addition, the development of a model in which mammary tumors develop in mice with the first year of life should be valuable in future studies of both the pathogenesis and treatment of this disease.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by NIH grant CA70490 (to
B. H. K.) and the Department of Defense USAMRMC grant
DAMD17-97-1-7102 (to V. L. C. and M. G. B.) 
2 To whom requests for reprints should be
addressed, at Department of Medicine, CB 7248, Thurston-Bowles
Building, UNC-Chapel Hill, Chapel Hill, NC 27599. E-mail: Treawouns{at}aol.com
3 The abbreviation used is: MMTV, mouse mammary
tumor virus.
Received 4/ 4/01. Accepted 7/ 3/01.
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REFERENCES |
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