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Molecular Biology and Genetics |
Program in Molecular and Cellular Biology [C. K., J. P., D. J. J.], and Department of Veterinary and Animal Sciences [G. D. H., D. J. J.], University of Massachusetts, Amherst, Massachusetts 01003, and Department of Pathology; Baystate Medical Center, Springfield, Massachusetts 01199 [S. P. N.]
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ABSTRACT |
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INTRODUCTION |
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Hormones are known to regulate the critical periods of breast development and susceptibility of the breast to tumorigenesis (5 , 7) . Treatment with estrogen and progesterone stimulated lobular-alveolar development and was shown to reduce the incidence of mammary tumor formation in rats (8) , whereas the protective effects of placental hormones have been associated with the activation of apoptosis (9) .
The p53 tumor suppressor gene is also important in the development of breast cancer because it is commonly mutated in tumors (10) . In normal cells, DNA damage leads to an accumulation of p53 protein in the nucleus, in which p53 acts as a transcriptional activator for a group of genes involved in cell cycle arrest, DNA repair, or apoptosis (11, 12, 13, 14) . It is in this manner that p53 serves to maintain the integrity of the genome. Germ line mutations in p53 have been shown to segregate with the Li-Fraumeni cancer susceptibility syndrome (15) , which confers on women an increased risk of developing breast cancer compared with the general population (15, 16, 17) . In addition, mutations in p53 have been detected in over 40% of spontaneous breast carcinomas (18 , 19) . These observations implicate p53 not only in the pathogenesis of breast cancer but in the susceptibility to it as well.
Therefore, in an attempt to understand the molecular mechanism responsible for the susceptibility of the mammary gland to tumorigenesis, the expression and functional status of p53 were examined in the normal mammary tissue after hormonal treatment in vivo. High levels of p53 protein were detected in the ductal epithelium of the mature mammary gland and were localized within the cytoplasm. In addition, p53 remained localized to the cytoplasm after radiation-induced DNA damage. However, treatment of mice with placental hormones resulted in the nuclear accumulation and activation of p53 in response to DNA damage. These results demonstrate that hormones can alter the functional status of p53 in the mammary gland.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-radiation (1 h postirradiation,
n = 2; 6 h postirradiation,
n = 4). Radiation was supplied by a
137Cs irradiator. Separate groups of 9-week
BALB/c and BALB/c-p53 knockout female mice were given 5 IU
of PMSG3
isolated from pregnant mares’ serum (Sigma, St. Louis, MO) followed by
5 IU hCG from human urine of pregnancy (Sigma) 48 h later. Animals
were then subjected to 5 Gy whole body -radiation 6 h after
injection with hCG and killed at 1 or 6 h postirradiation. Two
animals were evaluated at each time point corresponding to the
unirradiated time point and the 1- and 6-h postirradiation time
points. Vaginal smears were taken at the time of sacrifice to
evaluate the phase of the estrous cycle. Normal human breast tissue was
obtained from reduction mammoplasties at Baystate Medical Center
(n = 4). All of the tissues were fixed in
10% phosphate buffered formalin, rinsed in 70% ethanol, and embedded
in paraffin.
Northern Blot Hybridization.
Tissues were homogenized and total RNA was isolated and subjected to
Northern blot analysis as described previously (20)
.
Briefly, 10 µg of total RNA was separated on a 1.2%
agarose-formaldehyde gel, blotted onto a nylon membrane (Zetabind;
CUNO, Meriden, CT), and hybridized sequentially with
32P-labeled p53,
p21WAF1, and 18S cDNA probes.
Immunohistochemistry.
Four-µm sections were deparaffinized and subjected to antigen
retrieval (20)
. Sections were incubated overnight at 4°C
with rabbit polyclonal CM5 antisera (1:200; Novacastra, Newcastle upon
Tyne, United Kingdom), CM1 (1:200; Novacastra) or Ab-5 (1:50;
Oncogene Research, Cambridge, MA) specific for murine p53, human
p53, and murine p21/WAF1, respectively. Immunocomplexes were visualized
by the ABC method (Vector Laboratories, Burlingame, CA). Sections were
counterstained with methyl green.
In Situ End-Labeling Method.
Paraffin-embedded sections were deparaffinzed, treated with methanol
and hydrogen peroxide to quench endogenous peroxidases, and subjected
to TUNEL, using FragEL DNA Fragmentation kit (Oncogene Research).
Sections were counterstained with methyl green and analyzed for
apoptosis by counting a total of 2000–8000 cells per tissue (2–6
animals/treatment; 3–5 fields/animal). Differences in TUNEL-positive
cells among treatments were compared using a 99.95% confidence
interval test of 2 proportions.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). High levels of p53 mRNA were detected in the
resting mammary glands of mature nulliparous mice (N),
declined during lactation (L5), then were induced rapidly in
tissues undergoing intense apoptosis during involution (W2,
W5). Levels remained elevated into late involution
(W10). Despite similar levels of p53 mRNA in
nulliparous and postweaning tissues (N versus
W2), p21WAF1 was induced only
during the early postweaning period (W2–W5) when
nuclear p53 protein was detected in association with apoptosis
(20)
. Similarly, basal levels of other p53 target genes
(mdm2 and bax) were detected in nulliparous
mammary tissue despite high levels of p53 mRNA (data not
shown). High levels of p53 protein were also detected in nulliparous
mammary glands by immunoprecipitation-immunoblot analysis (data not
shown). This suggested that the differences in the transcriptional
activity of p53 in the nulliparous versus weaning-2-day
tissues were attributable to differences in the activity of p53
protein, not differences in abundance.
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)
and in 50% of normal human breast tissues (Fig. 1C
). The
cytoplasmic localization was not attributable to cross-reactivity
because mammary glands from age-matched BALB/c-p53 knockout
mice were devoid of immunostaining (Fig. 1D
). This suggested
that the high levels of wild-type p53 protein in the resting
nulliparous mammary gland are inactive because of cytoplasmic
sequestration and that the mechanism is conserved among humans and
mice.
Localization and Activity of p53 in Response to DNA Damage.
To determine whether the cytoplasmic p53 in the mammary epithelium
could be activated, whole-body -radiation was administered to
nulliparous female mice to induce p53-dependent responses (Fig. 2
). Transcriptional activation of target genes by p53 would require its
translocation to, and accumulation in, the nucleus after DNA damage
(21)
. However, at 1 h after irradiation, p53 remained
in the cytoplasm with no reactivity detected in the nuclei of the
mammary epithelium (Fig. 2A
). By 6 h after irradiation,
faint nuclear staining was detected in a few cells (<1%) of the
ductal epithelium, but the majority of p53 protein remained sequestered
within the cytoplasm (Fig. 2B
). In contrast, the epithelium
of the follicular hair bulges in the skin, and a substantial proportion
of lymphocytes (Fig. 2, C and D
) stained strongly
for nuclear p53 at 1 and 6 h postirradiation. Mammary tissue and
skin and the intramammary lymph node of irradiated knockout mice were
negative for p53 immunostaining (data not shown).
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). By 6 h after radiation
treatment, less than 1% of the cells expressed nuclear p21/WAF1
protein in the ductal epithelium (Fig. 2F
). Nuclear p21/WAF1
protein could be detected in some of the nuclei of the stromal
fibroblasts and adipocytes surrounding the ductal epithelium. In
contrast, the follicular bulbs and the intramammary lymph node stained
strongly for nuclear p21/WAF1 protein at 1 and 6 h after radiation
treatment (Fig. 2, G and H
). The mammary gland,
skin, and lymph node of BALB/c-p53 knockout mice were
negative for p21/WAF1 protein induction at 1 and 6 h
postirradiation, confirming the response as p53-dependent (data not
shown).
Levels of apoptosis were quantitated to determine whether biological
responses to p53 were impaired as well (Fig. 3A
). In the unirradiated mammary gland, 2.38% of mammary epithelial cells
were TUNEL-positive. Similarly, 0.07% of the follicular hair bulges in
skin and 1.94% of the intramammary lymphocytes were TUNEL-positive.
Apoptosis was increased greater than 10-fold in the follicular bulges
of the skin and the intramammary lymph node after -radiation
(P < 0.05) compared with a 1.5-fold
induction of TUNEL-positive cells in the mammary epithelium after
-radiation. Although the increase in apoptosis in the mammary
epithelium was modest compared with that observed for the other
tissues, these increases were statistically significant
(P < 0.05). These responses were
p53-dependent because there was no induction above basal apoptotic
levels in the tissues from BALB/c-p53 knockout mice after
irradiation. Thus, despite the expression of high levels of p53 protein
in the mammary epithelium of nulliparous BALB/c mice, p53-dependent
responses were impaired after genotoxic insult.
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). Therefore, mice were challenged with ionizing radiation
6 h post-hCG treatment, then analyzed 1 and 6 h later.
Nuclear p53 was detected in the ductal epithelium of the mammary gland
1 h after irradiation (Fig. 4B
). At 6 h
postirradiation, p53 remained localized to the nucleus of the
epithelial cells, with diffuse cytoplasmic p53 also evident (Fig. 4C
). However, there was a difference in the cell types that
expressed nuclear p53 at 1 h versus 6 h
postirradiation. At 1 h, both luminal and basal epithelial cells
within the ducts were positive for nuclear p53; yet, by 6 h
postirradiation, staining was more prevalent in the basal cells.
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). By six h postirradiation,
intense nuclear staining of p21 protein was detected in the majority of
the ductal epithelial cells (>60%) as well as in the surrounding
stroma (Fig. 4E
). Similar to the pattern of p53
immunostaining, there was a shift from luminal and basal cell
expression of p21/WAF1 at 1 h to a predominance of basal cell
expression at 6 h. The absence of p21/WAF1 in mammary glands of
BALB/c-p53 knockout mice postirradiation confirmed that the response
was p53-dependent (Fig. 4F
).
Levels of apoptosis were also measured in hormone-treated animals (Fig. 5A
). Basal levels of apoptosis in mammary gland, follicular hair bulges of
the skin and intramammary lymph node from unirradiated PMSG/hCG-treated
mice were 1.79, 0.40, and 2.07%, respectively. These apoptotic levels
were not significantly different from untreated, unirradiated tissues
in Fig. 3
(P > 0.05). Thus, the basal
apoptotic levels were not altered by the PMSG/hCG treatment alone.
However, hormone treatment followed by irradiation (PMSG/hCG + irradiation) increased the number of apoptotic cells in the
mammary epithelium to 8.8%. This represents a 4.9-fold induction of
apoptosis attributable to PMSG/hCG + irradiation which is significantly
greater (P < 0.05) than that observed with
irradiation alone (Fig. 3
). The hormonal treatment also enhanced the
apoptotic response to -radiation in follicular hair bulges but had
no affect on apoptosis in the lymph node (Fig. 3
versus Fig. 5
). The increase in apoptosis attributable to the hormones was
p53-dependent because apoptotic responses were not induced in mammary
glands from p53-knockout mice (Fig. 5A
). Thus, treatment
with placental hormones resulted in nuclear accumulation of p53 protein
in the mammary epithelium, transcriptional activation of target genes,
and apoptosis in response to ionizing radiation.
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DISCUSSION |
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). Cytoplasmic localization of wild-type p53
has been reported in breast tumors as well as other neoplasms and
embryonic stem cells (21, 22, 23, 24)
. In these diverse cell
types, nuclear exclusion has been associated with functionally inactive
p53. Similarly, responses to -radiation were largely absent in the
normal mammary epithelium compared with follicular hair bulbs of the
skin and the intramammary lymph nodes in vivo (Figs. 2
and 3
). Particular domains of the p53 protein have been demonstrated to be
critical for its localization to the nucleus. An exposed nuclear
localization signal and the tetramerization domain have been shown to
be necessary for nuclear import and retention, whereas, residues
Arg-306 and Lys-305, in addition to the cytoplasmic sequestration
domain, have been reported responsible for cytoplasmic sequestration
(25, 26, 27)
. These results suggest that the conformation of
p53 is important for its localization and ability to translocate to the
nucleus. In the murine mammary gland and normal human mammary
epithelial cells, p53 protein has been detected with the PAb240
monoclonal antibody, which recognizes a denaturation-sensitive epitope
(28
, 29) . Therefore, conformational shift is one mechanism
by which p53 may be sequestered in the cytoplasm of mammary epithelial
cells. This may involve either exposing the cytoplasmic sequestration
domain or concealing a domain critical for import and retention in the
nucleus. Cytoplasmic localization of p53 may also be a consequence of
conformation-independent mechanisms involving excessive export or
tethering of p53 by cytoplasmic proteins such as P53BP2 or hsp84
(30, 31, 32)
. Although the precise mechanism responsible for
cytoplasmic sequestration and impaired function of p53 in the quiescent
mammary epithelium remains to be established, we show that it is
reversible by exposure to hormones.
p53 Is Functionally Compromised in the Mammary Epithelium.
The p53 responses to ionizing radiation have been well documented
in vivo. Under normal conditions, p53 levels are below the
level of detection by immunohistochemistry and require very sensitive
methods to detect protein (33)
. Responses to -radiation
have been shown to vary widely among tissues and cell types. Some
tissues such as skin, intestinal epithelium, and lymphoid tissues
displayed an increase in protein accumulation, increased p53
transcriptional activity, and induction of apoptosis, whereas other
tissue types such as liver, skeletal muscle, and brain showed no
response (33, 34, 35)
. Previous studies had characterized the
apoptotic response to ionizing radiation in preneoplastic lesions
(36
, 37) , but p53 responses in the normal mammary gland
had not been fully characterized.
In the present study, we demonstrated that p53-dependent responses to
-radiation in the mammary epithelium differed from skin and
lymphocytes (Fig. 2
). In the mammary epithelium, p53 was localized to
the cytoplasm of the ductal epithelium, with little induction of
p21/WAF1 or apoptosis after -radiation (Fig. 2
& 3
). Previous
studies have reported a spontaneous apoptotic index of less than 1% in
nulliparous BALB/c mice, with an increase to 
3% after
-irradiation (36)
, which was similar to the results
observed in Fig. 3
. Although modest, induction of apoptosis in response
to DNA damage in the nulliparous mammary epithelium was observed in
both studies.
Activation of p53 by Placental Hormones.
Epidemiological studies have established that pregnancy exerts a
prophylactic effect against breast cancer (7)
. The
mechanism by which pregnancy exerts this protective effect is not
clear; however, ovarian and placental hormones have been shown to mimic
these effects by causing differentiation of the mammary epithelium
similar to a pregnant state (8
, 38, 39, 40)
. Apoptotic
responses play a pivotal role in rendering the gland resistant to
tumors because apoptotic responses to -radiation were greater in
pregnant mammary glands compared with the nulliparous gland
(36)
. Treatment with placental hormones also rendered the
mammary gland resistant to tumor development and increased
apoptotic responses after carcinogen-induced DNA damage
(9)
. Therefore, hormonal status affects susceptibility to
tumor development and apoptotic responses.
On the basis of these associations, placental hormones were used to
modify p53-dependent responses to DNA damage. Irradiation of mice
6 h after hCG treatment allowed us to evaluate the immediate
effects of the hormones rather than the secondary effects attributable
to differentiation, which occur later and would complicate the
interpretation. Mice treated with PMSG and hCG showed nuclear
localization of p53 protein and p21/WAF1 at 1 h postirradiation
(Fig. 4
) followed by a 5-fold induction of apoptotic responses at
6 h (Fig. 5
). Although -radiation-induced apoptosis in the
intramammary lymph nodes was not affected by hormonal treatment,
apoptotic responses were increased in the follicular hair bulbs.
Therefore, the effects of hormonal treatment on the activity of p53 may
not be limited to the mammary epithelium. These data suggest that
placental hormones promoted nuclear accumulation of p53 protein within
the mammary epithelium, which mediated p53-dependent induction of
p21/WAF1 and apoptosis after DNA damage, whereas responses to DNA
damage were minimal in untreated mice (Fig. 3
). Furthermore, the
effects were rapid and preceded the differentiation of the mammary
epithelium.
Treatment with PMSG and hCG is used to induce superovulation and is known to cause complex hormonal changes affecting ovarian and pituitary feedback mechanisms (41) . As a result, the effects on p53 function may be attributable to the combined actions of gonadotropins, steroids, and peptide hormones. Vaginal smears from PMSG/hCG-treated mice revealed cornified epithelium indicative of estrus phase (41) . Therefore, high levels of endogenous estrogen were present in the mice at the time of irradiation. Estrogen may cause the activation of p53 function in the mammary epithelium inasmuch as it has been shown to increase the levels of p53 protein in estrogen receptor-positive mammary epithelial cell lines (42) and activate the P1 promoter in the p53 gene (43) . However, direct effects of the exogenous hCG cannot be ruled out because receptors for hCG have been found on rat and human mammary epithelial cells (44 , 45) , and hCG may not be cleared within the 6–12 h period postinjection analyzed in these experiments. Furthermore, p53-dependent activation of apoptosis and growth inhibition by hCG have been observed in both human breast epithelial cells and rat mammary epithelial cells (9 , 38 , 39 , 46) . The exact hormone(s) necessary for the altered p53 response in the mammary gland remains unclear. Nevertheless, the lack of p53 activity in the nulliparous mammary epithelium could be reversed by hormonal stimulation.
The relationship between hormonal stimuli and the pattern of p53 expression may, in fact, be quite complex as suggested by the absence of cytoplasmic p53 in 50% of normal breast samples. This may be attributable to the phase of the menstrual cycle or the hormonal status of the individuals at the time of surgery. The use of oral contraceptives, hormone replacement therapy, or the menopausal state of a woman could also account for more variable expression and localization of p53 in human breast tissues.
Hormonal Control of p53 Function and Chemoprevention.
Overall levels of p53 in the mammary epithelium may influence
susceptibility to tumor formation. Reduction in levels of p53 was shown
to be sufficient to enhance tumor formation in the thymus of mice
heterozygous for p53 (47)
. Complete loss of
p53 in the mammary epithelium rendered the mammary
epithelium extremely sensitive to tumor formation (48)
.
Therefore, the compromised function of p53 observed in normal resting
mammary epithelium in nulliparous mice may contribute to the heightened
susceptibility of the gland to tumorigenesis. Russo et al.
(4)
demonstrated that the mammary epithelium was unable to
repair its DNA after carcinogenic insult. Therefore, compromised
function of p53 provides a molecular mechanism that may be responsible
for impaired DNA repair and apoptosis in the nulliparous mammary
epithelium leading to heightened susceptibility to mammary tumors.
Susceptibility of the mammary epithelium is also influenced by endocrine status. Likewise, p53 function was shown to be subject to hormonal regulation. Treatment with PMSG and hCG activated p53 function, which could render the mammary epithelium less susceptible to DNA damage. Clearly, identification of the hormone(s) responsible for the functional activation of p53 will be necessary to fully understand the mechanism of p53 regulation in the mammary epithelium. Hormonal therapies designed to activate p53 may provide an effective prophylactic therapy as well as a means to increase the efficacy of chemotherapy by diminishing DNA damage in surrounding normal epithelium while increasing the responsiveness of breast tumors with wild-type p53.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by grants from the
Massachusetts Department of Public Health (34088PP1017), the National
Cancer Institute, NIH (CA66670), and the United States Department of
Agriculture (Hatch Project 707). 
2 To whom requests for reprints should be
addressed, at the Department of Veterinary & Animal Sciences, Paige
Laboratory, University of Massachusetts, Amherst, MA 01003. Tel: (413)
545-5335; FAX: (413) 545-6326; E-mail: jjerry{at}vasci.umass.edu
3 The abbreviations used are: PMSG, pregnant mare
serum gonadotropin; hCG, human chorionic gonadotropin; TUNEL, terminal
deoxynucleotidyl transferase dUTP nick end-labeling.
Received 8/ 9/99. Accepted 3/24/00.
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