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Department of Experimental Pathology, Roswell Park Cancer Institute, Buffalo, New York 14263 [C. I.]; Center for Nutrition in the Prevention of Disease, AMC Cancer Research Center, Denver, Colorado 80214 [H. J. T.]; and Department of Nutritional Sciences, University of Wisconsin, Madison, Wisconsin 53706 [H. E. G.]
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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60%. Interestingly, this
was not accompanied by decreases in BrdUrd labeling or the proportion
of IDP cells expressing PCNA and cyclin D1. An enhancement
in the fraction of p27/Kip 1-positive IDP cells, however, was detected
as a result of Se-methylselenocysteine treatment.
Although triphenylselenonium chloride did not reduce the total number
of IDPs, there were more of the smaller-sized lesions and fewer of the
larger-sized lesions compared with those found in the control group.
Triphenylselenonium chloride also significantly decreased the
proportion of IDP cells incorporating the BrdUrd label or expressing
PCNA and cyclin D1. The above findings suggest that early
transformed cells are sensitive to selenium intervention, whereas
normal proliferating cells are not. It is possible that
Se-methylselenocysteine blocks carcinogenesis by a
pathway that may not involve cell growth inhibition as a primary
response; in contrast, triphenylselenonium chloride is likely to act by
a cytostatic mechanism. The data also imply that selenium efficacy
testing in intervention trials is possible with the use of biomarkers,
provided that the appropriate biomarkers are matched with the selenium
compound of interest and that the pathological characteristics of the
cell population to be evaluated are taken into consideration. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Over the past decade, our collaborative group has been focusing our attention on two selenium compounds in particular, i.e., Se-methylselenocysteine and triphenylselenonium chloride, and has published a number of reports on their in vivo cancer-protective activities (12, 13, 14, 15, 16, 17, 18, 19) . Se-methylselenocysteine is a water-soluble prodrug designed to deliver a monomethylated selenium metabolite, which we believe to be a critical intermediate in selenium chemoprevention (11 , 20) . This selenoamino acid is also found naturally in selenium-enriched plants (21, 22, 23) . Triphenylselenonium chloride is a synthetic compound with a cationic selenium atom bonded directly to three unsubstituted benzene rings; therefore, it is a very stable molecule that is not likely to release bioavailable selenium (19) . Despite the lipophilic nature of the benzene rings, triphenylselenonium chloride is water soluble because of the positive charge. Previous studies have shown that both Se-methylselenocysteine and triphenylselenonium chloride are effective against rat mammary gland carcinogenesis, although their dose responses are quite different (12 , 16) . When given in the diet, the levels of Se-methylselenocysteine and triphenylselenonium chloride required to attain 50% inhibition of tumor yield are about 2 and 20 ppm selenium, respectively. We also have indirect evidence suggesting that these compounds might exert their chemopreventive effects by different modes of action (18 , 24) .
In the first part of the present study, we compared the effects of Se-methylselenocysteine and triphenylselenonium chloride on cell proliferation and the expression of cell cycle biomarkers in the mammary gland of pubescent female rats. Cell proliferation in defined mammary gland structures, i.e., TEBs3 and alveoli, was assessed by BrdUrd labeling. Three different cell cycle biomarkers were also determined: PCNA, cyclin D1, and p27/Kip 1 (an inhibitor of cyclin-dependent kinase). In the rat model, TEBs are the primary sites for the chemical induction of mammary adenocarcinomas (25) . Within 2–3 weeks after carcinogen dosing, enlargement of the TEB, characterized by a localized piling up of intraductal cells, is detectable in histological sections. Throughout the mammary gland, the cells in selective TEBs continue to proliferate until they completely fill up the duct. These early transformed lesions, which are known as IDPs, are the precursors for the eventual formation of palpable carcinomas (26) . Therefore, the second part of this study was aimed at: (a) quantifying the number of IDPs in the mammary gland of rats that were treated with a single dose of methylnitrosourea and then were given either Se-methylselenocysteine or triphenylselenonium chloride; and (b) determining the changes in cell proliferation and the expression of cell cycle biomarkers in these IDPs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Quantification of IDP Lesions.
Each mammary gland whole mount was divided into six segments and
embedded into paraffin blocks. Ribbons of 5-µm thickness were cut
from each block and placed on slides that had been treated with
3-aminopropyltriethoxysilane. Every tenth section was heat immobilized,
deparaffinized in xylene, rehydrated in descending grades of ethanol,
and stained with H&E. These H&E slides were examined under the
microscope for the appearance of IDP lesions using the criteria
described by Russo et al. (25)
. Once a section
showing the pathology of an IDP lesion was found, the in-between slides
were similarly stained to confirm the histology. Thus, the size of each
IDP lesion could be estimated operationally by the number of serial
sections showing the same pathology. The total IDP count data were
analyzed by the 
2 test using a Poisson
regression model (27)
.
Immunohistochemical Staining of BrdUrd, PCNA, Cyclin
D1, and p27/Kip 1.
Antibodies for immunohistochemical staining of mammary gland sections
were obtained commercially: mouse anti-BrdUrd from Becton Dickinson,
mouse monoclonal anti-PCNA and anti-p27/Kip 1 from Santa Cruz
Biotechnology, and mouse anti-cyclin D1 (clone
DCS-6) from Neomarkers. These antibodies were applied at the following
dilutions and exposure times: anti-BrdUrd at 1–40 for 60 min,
anti-PCNA at 1–20,000 for 60 min, anti-cyclin D1
at 1–200 for 30 min, and anti-p27/Kip 1 at 1–50 for 60 min. The
procedure of immunohistochemical staining was described in detail in a
previous publication (28)
and is briefly recapped here.
After the tissue sections were incubated with the primary antibody at
room temperature in a humid chamber, they were treated with a
biotinylated rabbit secondary antibody against mouse immunoglobulin.
This was followed by the addition of streptavidin horseradish
peroxidase, which binds to biotin. Diaminobenzidine was used as the
chromogen to generate a precipitate that is brown because of its
reaction with peroxidase. All slides were counterstained with
hematoxylin, rinsed, dehydrated, and mounted with Permount. Cells
expressing the antigen were identified by a brown stain over the
nucleus. The numbers of slides evaluated per rat were indicated in the
footnotes of the tables presented in "Results." Color pictures were
taken with a camera mounted on top of the microscope. All hard-copy
images were coded so that the person analyzing the data was blinded to
the group assignment to avoid bias. Because immunohistochemical
staining for a protein is not stoichiometric relative to the amount of
protein present, differences in staining were analyzed by using a
Kruskal-Wallis rank test (28)
.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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summarizes the results of BrdUrd labeling, PCNA, cyclin
D1, and p27/Kip 1 expression in TEB cells and
alveolar cells of the developing mammary gland. The BrdUrd label and
the three cell cycle-associated proteins all showed a distinctive
nuclear localization; hence, the positively stained cells could be
easily quantified from hard-copy color images. The data are expressed
as the percentage of cells in each type of structure that were
positively stained. For the TEB results, the analysis was based on
counting a total of six to eight structures (each structure consisted
of 100–200 cells) per rat, with six rats/group. For the alveoli
results, six to eight slides were evaluated per rat, and each field
usually displayed a range of 100–250 cells. As noted in "Materials
and Methods," selenium supplementation to these animals was given
during a period of rapid development of the mammary gland in which the
cells remain highly proliferative. At the time of sacrifice, the
animals were about 50 days of age. The data showed that neither
Se-methylselenocysteine nor triphenylselenonium chloride
significantly affected the activity of cell proliferation (as
determined by BrdUrd labeling) or the expression of cell cycle
biomarkers (as assessed by PCNA, cyclin D1, and
p27/Kip 1) in the two types of differentiated mammary gland structures.
The consistency of the data strongly suggests that neither compound is
inhibitory to cell growth during the process of normal tissue
morphogenesis and differentiation.
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presents a composite picture of the histology of IDP progression. Fig. 1A
shows a normal TEB. At 2–3 weeks after MNU dosing, cells
at the tip and neck of the TEB begin to proliferate and invade into the
cavity of the ductal structure (Fig. 1, B and C
).
A cross-section of a partially filled duct is depicted in Fig. 1D
. The development of the IDP continues until the lumen of
the duct is almost completely occupied, as seen in a longitudinal
section in Fig. 1E
and in a cross-section in Fig. 1F
. As noted in "Materials and Methods," the size of
each IDP lesion was estimated by the number of serial sections showing
the typical pathology, which was represented by Fig. 1
, C–F.
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shows the quantitative IDP results from MNU-treated rats that were
given either Se-methylselenocysteine or triphenylselenonium
chloride. The histology of the mammary gland sections was evaluated at
6 weeks after carcinogen administration. In addition to obtaining a
total count of these lesions in the abdominal-inguinal mammary gland
chain, the size of each lesion was also determined operationally by the
number of serial sections showing the same pathology. There were 57
IDPs found in a total of six rats in the control group (last column of
Table 2
). Treatment with Se-methylselenocysteine reduced the
number of IDPs by 60% (P < 0.05). In contrast,
triphenylselenonium chloride did not seem to have much of an effect in
diminishing the population of the IDPs. All of the lesions were
categorized into five size classes with each containing 
10, 11–20,
21–30, 31–40, or >40 serial sections, respectively. To analyze the
size distribution data, a repeated measures option was added to the
Poisson regression because most animals presented lesions in more than
one size class. No significant differences were found by treatment
within a given size class, probably because of the small sample number
in each category when the data were segregated; this reduced
statistical power to detect significant differences attributable to
treatment. However, it is noteworthy to point out that in the
triphenylselenonium chloride-treated rats, there was a trend of a low
abundance of the larger-sized lesions and a high yield of the
smaller-sized lesions. For example, there were altogether 17 lesions of
>21 sections in the triphenylselenonium chloride group compared with
35 in the control group. Conversely, there were 36 lesions of <20
sections in the triphenylselenonium chloride group versus 22
in the control group. Overall, the data suggest that treatment with
Se-methylselenocysteine reduces the number of IDPs uniformly
across all size classes, whereas triphenylselenonium chloride seems to
slow down the expansion of these transformed colonies without having
much of an effect in blocking their genesis.
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100 days of age. At this stage of the
life span of a rat, the mammary gland has essentially completed its
development. The mammary tree of an adult rat consists mainly of a
network of subtending branches comprising numerous alveolar clusters,
with very few of them ending in TEBs. When we examined the data on
BrdUrd labeling, PCNA, cyclin D1, and p27/Kip 1
in the alveolar cells of the fully matured mammary gland, we again
could not detect any effect on these end points attributable to either
Se-methylselenocysteine or triphenylselenonium chloride. In
other words, the finding was similar to that reported in Table 1
.
Because all of the data are negative, we did not feel compelled to
include them in this report. The only difference in the assay results
between the 50-day-old rats and the 100-day-old rats was the higher
proportion of cells that were positively stained for BrdUrd, PCNA, and
cyclin D1 in the former group. This was to be
expected because the mammary gland is still actively developing in the
younger animals.
Because the biomarker data from the IDPs are the focus of this study,
some representative staining patterns in these structures are included
in Fig. 2
. It is not easy to identify a set of 12 "typical" pictures based on
three treatment groups and four different assays because the final
results were obtained by evaluating a total of 12–15
slides/group/assay. Thus, Fig. 2
panels A–D are presented
to illustrate the immunohistochemistry of BrdUrd, PCNA, cyclin
D1, and p27/Kip 1, respectively, with the
objective of demonstrating: (a) the variability in the
proportion of positively stained cells for the four different
antibodies (highest for cyclin D1 and lowest for
BrdUrd); (b) the nuclear localization of all four antigens
of interest; and (c) the distribution of stained cells in a
representative IDP section.
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shows the proliferation and biomarker results in mammary gland IDPs
from control and selenium-treated rats. It is interesting to note that
Se-methylselenocysteine and triphenylselenonium chloride
produced differential effects on these parameters. With BrdUrd
labeling, it was found that Se-methylselenocysteine only
marginally reduced the activity of DNA synthesis (not statistically
significant), whereas triphenylselenonium chloride caused a healthy
40% decrease (P < 0.05). With the cell cycle
biomarker assays, Se-methylselenocysteine significantly
increased (P < 0.05) the percentage of cells
expressing p27/Kip 1 but did not appear to modulate the proportion of
cells that was stained positive for either PCNA or cyclin
D1. In contrast, triphenylselenonium chloride
suppressed the proportion of cells that was positive for PCNA and
cyclin D1 but not the proportion of the p27/Kip
1-expressing cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The lack of an effect of Se-methylselenocysteine on PCNA and
cyclin D1 in IDP cells is consistent with the
BrdUrd results. However, this observation appears to be in disagreement
with the finding of cell cycling disruption by Se-methylselenocysteine
in vitro (6)
. The discrepancy highlighted the
need to examine both the in vitro and in vivo
effects of a specific selenium compound. We were intrigued by the
increased expression of p27/Kip 1 caused by
Se-methylselenocysteine treatment, as shown in Table 3
. This
protein acts during the G0 and the early
G1 phases of the cell cycle by inhibiting cyclin
D1-cyclin-dependent kinase 4 and cyclin
E-cyclin-dependent kinase 2 complexes (29)
. In addition to
interfering with cell cycle transit, p27/Kip 1 is known to be involved
in differentiation programs of many cell types, both in tissue culture
and in vivo (30, 31, 32, 33, 34)
. Thus, p27/Kip 1 may have
other tumor suppressor functions. When p27/Kip 1 is determined in
clinical tumor samples using immunohistochemical assays, the low or
absent expression of this protein generally signals a poor prognosis of
disease progression (35)
.
In a previous study, we reported that treatment of animals with selenium-enriched garlic for 1 month immediately after carcinogen administration was just as effective in mammary cancer prevention as the 5-month continuous treatment regimen (24) , suggesting that the selenium compound in garlic may irreversibly alter the process of clonal expansion of transformed cells during their early stage of development. It has since been found that selenized garlic contains Se-methylselenocysteine as the predominant form of selenium (23) and that pure Se-methylselenocysteine produced the same effect as selenized garlic.4 A possible mechanism to reduce the population of IDPs is by apoptosis. Selenium is a potent inducer of apoptosis in a number of in vitro cell models (2 , 3 , 5 , 36, 37, 38, 39) . For cells that have sustained irreparable DNA damage, apoptosis is a means for their elimination. The appearance of a defined premalignant lesion (e.g., an IDP) is the net result of cell proliferation minus cell death. Thus, a down-sizing in the population of premalignant lesions can be achieved, in effect, by enhancing cell death either in the absence of or in addition to decreasing cell proliferation. We have preliminary data indicating that Se-methylselenocysteine is able to induce apoptosis in IDP cells in vivo, particularly in the smaller colonies.5 This research finding will be the subject of a separate publication.
Contrary to Se-methylselenocysteine, triphenylselenonium chloride does not reduce the population of IDPs but seems to suppress clonal expansion of these lesions. Thus, in tri-phenylselenonium chloride-treated rats, the IDPs appeared to be smaller, and BrdUrd labeling as well as the expression of PCNA and cyclin D1 in IDP cells was concomitantly depressed. These findings are congruent with our previous report that suggests that triphenylselenonium chloride inhibits tumorigenesis by a cytostatic mechanism that involves retarding the progression of premalignant to malignant lesions (18) . Interestingly, the in vitro effect of triphenylselenonium chloride is also characterized by cytostasis, i.e., a decrease in cell proliferation attributable to inhibition of DNA synthesis (10) . Thus, with this compound the in vitro and in vivo responses with respect to cell proliferation control are more in line with each other.
Our study demonstrates convincingly that neither Se-methylselenocysteine nor triphenylselenonium chloride affected the growth of normal, untransformed cells in the mammary gland. The finding was reproduced both with the actively developing mammary gland of pubescent rats and with the matured mammary gland of adult rats. Thus, the effects of both compounds were manifested only in premalignant lesions. This implies that normal cells are not sensitive to selenium intervention, whereas early transformed cells express certain defective signaling pathways that can be overcome by specific chemical forms of selenium. The fact that normal cells are resistant to growth inhibition by selenium is desirable; however, it makes tissue sampling a more difficult task in terms of collecting the suitable specimen for biomarker studies. Our data offer a glimmer of encouragement that the assay of biomarkers may be a feasible means for assessing the efficacy of selenium in cancer prevention trials, provided that the appropriate biomarkers are matched with the selenium compound of interest and that the pathological characteristics of the cells to be evaluated are taken into consideration. These criteria must be met for the results to be interpretable.
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Acknowledgments |
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Footnotes |
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1 Supported by Grants CA 61763 and CA 27706 from
the National Cancer Institute, NIH, and Roswell Park Cancer Institute
Core Grant CA 16056. 
2 To whom requests for reprints should be
addressed, at Department of Experimental Pathology, Roswell Park Cancer
Institute, Elm and Carlton Streets, Buffalo, NY 14263. Phone:
(716) 845-8875; Fax: (716) 845-8100; E-mail: cip{at}sc3101.med.buffalo.edu
3 The abbreviations used are: TEB, terminal end
bud; BrdUrd, bromodeoxyuridine; PCNA, proliferating cell nuclear
antigen; IDP, intraductal proliferation; MNU, methylnitrosourea.
Received 8/ 2/99; revised 10/22/99; accepted 11/ 6/99.
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References |
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-L-glutamyl-Se-methylseleno-L-cysteine and Se-methylseleno-L-cysteine. Biochim. Biophys. Acta, 192: 185-190, 1969.[Medline]
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