1 Department of Molecular and Cellular Oncology, The University of Texas M. D.
Anderson Cancer Center, Houston, TX 77030, USA
2 Department of Biochemistry and Molecular Biology, The University of Texas M.
D. Anderson Cancer Center, Houston, TX 77030, USA
* Author for correspondence (e-mail: rkumar{at}mdanderson.org)
Accepted 8 March 2004
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SUMMARY |
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Key words: Mammary gland development, Transgenic mice, MTA1, Progesterone receptors, Cyclin D1, Bcl-XL, Bcl2l1
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Introduction |
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However, these phenotypes are not limited to PR-A transgenic mice, as the
deregulation of other regulatory gene products such as cyclin D1, a regulator
of cell cycle progression, also causes hyperplasia
(Wang et al., 1994). In
particular, cyclin D1 directly activates ERs in a ligand-independent manner
(Zwijsen et al., 1998
).
Results from cyclin D1 knockout mice suggest an essential role of cyclin D1 in
the development of mammary glands (Fantl
et al., 1999
). Together, these observations indicate that cyclin
D1 may constitute an important downstream target of diverse upstream signals
in normal mammary gland development.
Because chromatin remodeling plays an essential role in the expression of
genes, factors that control chromatin remodeling in the vicinity of ER-target
promoters are likely to play an important role in the development of both
normal mammary gland and breast cancer. One such ER co-modulator is
metastasis-associated protein 1 (MTA1), originally identified as an
overexpressed gene in rat metastasis tumors
(Toh et al., 1994). In in
vitro models, MTA1 has been shown to interact with ER
and inhibits
estradiol-induced stimulation of ER transactivation function
(Mazumdar et al., 2001
). MTA1
overexpression in breast cancer cells also correlates with aggressive
phenotypes (Kumar et al.,
2003
). It is not clear, however, what role MTA1 plays in the
context of complete mammary gland development. To determine the effects of
MTA1 during postnatal mammary gland development, we have generated transgenic
mice expressing MTA1 under the control of the mouse mammary tumor virus long
terminal repeat (MMTV). We observed that MTA1 dysregulation in mammary
epithelium caused increased cell proliferation, hyper-branched ductal
structure formation and precocious development, and resulted in the
development of hyperplastic nodules and mammary gland tumors in virgin
mice.
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Materials and methods |
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RT-PCR and northern blot analysis
RT-PCR was performed using the Access Quick reverse transcription RT-PCR
system (Promega, Madison, WI) according to the manufacturer's instructions.
Primers for PR total were forward (5'-CTGGGGTGGAGGTCGTACAAG) and reverse
(5'-ACCAATTGCCTTGATCAATTCG); for PRB primers were forward
(5'-TCGTCTGTAGTCTCGCCTATACCG) and reverse
(5'-CGGAGGGAGTCAACAACGAGT). RNA was extracted from frozen tissues using
Trizol reagent (Invitrogen, Carlsbad, CA), denatured, analyzed on a 1% agarose
gel containing 6% formaldehyde and transferred to a nylon membrane. The blots
were hybridized with MTA1 cDNA probe and developed by autoradiography.
Immunoblot analysis
Total protein extracts of mammary gland were prepared and western blot
analysis carried out using primary mouse antibodies against cyclin D1 (1:1000;
Santa Cruz Biotecnology, Santa Cruz, CA); ß-casein, progesterone receptor
(PR) Ab-4 (1:100; Neomarkers, Fremont, CA); mouse PR (1:500 Novocastra
Laboratories, UK); ß-catenin (1:500, BD Transduction Laboratories,
Lexington, KY); anti-cytokeratin18 (1:100; Progen, Heidelberg, Germany); and
rabbit polyclonal BCL-X s/l (L-19) (1:100; Santa Cruz Biotechnology, Santa
Cruz, CA). Secondary antibodies consisted of anti-mouse and anti-rabbit
antibodies (both 1:2000) conjugated to horseradish peroxidase and visualized
by an enhanced chemiluminescence system. Densitometry was performed using a
computerized densitometer and proteins were quantitated from the images using
Sigma gel software (Sigma, St Louis, MO)
Mammary gland whole mounts, histology and immunodetection
For whole-mount analysis, number 4 inguinal mammary glands were stained
with carmine alum, as previously described
(Bagheri-Yarmand et al., 2003).
Briefly, the glands were fixed with acetic acid/ethanol (1:3) for 2 hours and
stained with 0.5% carmine/0.2% aluminum potassium sulfate for 16 hours. After
briefly being rinsed with distilled water, the mammary glands were dehydrated
using graded ethanol, and lipids were removed with two changes of acetone.
Finally, the glands were preserved in methyl salicylate. For histological
analysis, mammary-gland tissue was fixed in 10% neutral buffered formaldehyde
and embedded in paraffin wax according to standard methods. Sections (4 µm)
were stained with Hematoxylin and Eosin. For immunostaining, deparaffinized
sections were subjected to antigen retrieval. This involved boiling the
sections for 10 minutes and gradually cooling them for 30 minutes in 10 mM
citric acid buffer (pH 6.0). Sections were then incubated with rabbit
polyclonal PR-IgG (1:100; DAKO, Carpinteria, CA) followed by incubation with
biotin-conjugated anti-rabbit or anti-mouse secondary antibody. To
specifically detect PR-A forms in IHC, we used previously characterized hPRa7
(1:50; Neomarkers, Fremont, CA). Immunostained sections were lightly
counterstained in Hematoxylin according to the manufacturer's instructions,
dehydrated in graded ethanol, cleared in xylene and mounted on a coverslip
with peramount.
BrdU labeling and TUNEL assays
To detect bromodeoxyuridine (BrdU)-positive cells, a sterile solution of
5-bromo-2'-deoxyuridine (BrdU) (20 mg/ml; Sigma-Aldrich) in PBS (pH 7.4)
was administered to mice by intraperitoneal injection (50 mg/kg). Mammary
glands were harvested after 3 hours, embedded in paraffin wax and sectioned.
BrdU incorporation was detected by immunohistochemistry using a mouse
anti-BrdU monoclonal antibody as previously described
(Tonner et al., 2002).
Apoptosis was detected in paraffin wax sections by terminal deoxynucleotidyl
transferase-mediated dUTP-biotin nick-end labeling (TUNEL) analysis with
terminal deoxynucleotidyl transferase (Roche Diagnostics), as previously
described (Gavrieli et al.,
1992
). Ten random fields per section were documented by
photomicroscopy, and the percentage of TUNEL-positive epithelial cell nuclei
relative to the total number of epithelial cell nuclei was calculated. Mean
values were determined from results from at least six different mice.
Statistical analysis and reproducibility
Results are expressed as the mean±s.e.m. Statistical analysis of the
data was performed using a Student's t-test. The presented phenotypic
changes were documented in MTA1-TG founder lines 30, 31 and 33.
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Results |
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Isoform-selective modulation of progesterone receptor expression by the MTA1-TG
It is generally accepted that appropriate cellular responsiveness to
progesterone depends on the regulated expression and/or activity of the two
forms of PR. Thus, inappropriate progesterone signaling caused by an imbalance
in the expression and/or activities of the two forms of PR could lead to an
aberration in normal mammary gland development
(Soyal et al., 2002). Because,
as previously discussed, we discovered that the phenotypes of MTA1-TG mice
resemble those of PR-A TG mice (extensive lateral branching)
(Shyamala et al., 1998
), we
next attempted to determine whether the extensive side branching in MTA1-TG
mice glands was caused by regulation of the PR isoform by MTA1. To do so, we
examined the levels of PR transcripts by RT-PCR. Because the only difference
between PR-A and PR-B is in their C-terminal region, we designed primers that
are specific for PR-B or for total PR (Fig.
6A). Interestingly, RT-PCR showed a marked reduction in PR-B
transcripts in the MTA1-TG mammary glands, compared with wild-type glands,
suggesting an increase in the level of PR-A transcripts
(Fig. 6A). Immunoblot analysis
to show the status of PR isoforms also revealed upregulation of the PR-A
isoform in the virgin mammary glands from MTA1-TG mice
(Fig. 6B). We were unable to
detect either progesterone receptor isoforms in wild-type mice, possibly
because of the low levels in total lysate of mammary gland
(Schneider et al., 1991
). In
brief, the observed up regulation of PR-A and a downregulation of PR-B in the
transgenic mammary gland may partially account for the lack of hormonal
dependency for growth in the virgin gland and for the delayed or retarded
development of alveolar-lobular structures during pregnancy.
|
To define the effect of MTA1 on the PR pathway, we next used stable MCF-7
(Fig. 6E) or HC11 mouse
epithelial cell clones expressing T7-tagged MTA1 or control vector
(Fig. 6F). HC11 is a clonal
mammary epithelial cell line that was isolated from the mammary glands of mid
pregnant BALB/c mice which express estrogen receptor
(Ball et al., 1988;
Faulds et al., 2004
). We
examined the status of the PR isoform in MCF-7/MTA1 stable clone #25
(Fig. 6G). The MCF-7/MTA1
clones showed a reduced level of the PR-B isoform compared with the control
MCF-7/vector cells (Fig. 6G),
suggesting a change in the ratio of PR isoforms. The levels of B isoform were
also reduced in HC11/MTA1 cells when compared with the levels in
vector-transfected HC11 cells (Fig.
6H). In brief, these findings suggested that MTA1 promotes
selective downregulation of PR-B, and an alteration in the ratio of PR-A and
PR-B isoforms.
Impaired cyclin D1 and Bcl-XL expression in MTA1-TG mice
Because cyclin D1 is a major G1 cyclin expressed in mammary epithelial
cells and because the mammary glands of pregnant cyclin D1 knockout females
exhibited a defect similar to that in MTA1-TG females
(Fantl et al., 1999), we
examined cyclin D1 expression in mammary glands of wild-type and MTA1-TG. We
found that cyclin D1 expression in 12-week-old virgin MTA1-TG mice was two- to
threefold greater than that in wild-type mice
(Fig. 7A). By contrast, there
was about a 50% reduction in the cyclin D1 level at day 15 of pregnancy in
MTA1-TG compared with that in wild-type mice
(Fig. 7A). At lactation day 2,
the reduction in cyclin D1 expression was even more dramatic
(Fig. 7A). These results
suggested that the proliferation defect in the MTA1-TG mammary epithelium of
pregnant mice was due to impaired cyclin D1 expression. However, cyclin D1 was
upregulated in the MCF-7/MTA1 clones, similar to MTA1-virgin mammary gland
(Fig. 7B). In breast cancer
cells, although some genes are regulated by progesterone through both PR
isoforms, most genes are uniquely regulated through one or the other isoform
and predominantly through PR-B. Expression of the gene encoding the
anti-apoptosis protein Bcl-XL is uniquely regulated by PR-A
(Richer et al., 2002
). We
reasoned that regulation of PR isoforms in MTA1-overexpressing cell lines
might affect the expression of PR downstream target genes. We observed that
Bcl-XL levels were increased in MTA1-transgenic mice during virgin
and pregnancy and lactation (Fig.
7C). The HC11/MTA1 cells also showed increased levels of
Bcl-XL (Fig.
7D).
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Discussion |
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Analysis of mammary glands of virgin MTA1-TG mice revealed precocious
lobuloalveolar development and increased levels of the milk protein
ß-casein. The MTA1 transgene may induce precocious development by
extending the lifespan of differentiated mammary epithelial cells with each
estrous cycle, hence causing differentiated mammary epithelial cells and
milk-secreting lobuloalveoli to accumulate. Our finding that the
ß-catenin level was increased in virgin MTA1-TG mice is consistent with
results from a previous study of MMTV-N89 ß-catenin and MMTV-cyclin D1
showing precocious mammary gland development
(Wang et al., 1994;
Imbert et al., 2001
). In
addition, the early morphogenic phenotype of MTA1-TG mammary gland also
resemble to mammary phenotype found in MMTV-Wnt1 transgenic mice which induce
ductal hyperbranching, adenocarcinomas in females and male ductal extension
(Tsukamoto et al., 1988
).
We further found that MTA1 expression in the mammary epithelium resulted in
the downregulation of the PR-B isoform and upregulation of the PR-A isoform.
This has been consistent with the findings that the introduction of additional
PR-B isoform prematurely arrests ductal growth without altering the potential
for lobuloalveolar growth (Shyamala et
al., 2000). In addition, despite a robust lobuloalveolar growth in
the transplants of PR-B transgene mammary glands, there was a limited lateral
ductal branching and almost no functional differentiation
(Shyamala et al., 2000
). Thus,
the increased ductal growth and lateral branching seen in virgin glands of
MTA1-TG mice could be caused by downregulation of PR-B. Another interesting
feature of mammary epithelium in MTA1-TG mice was its resemblance to that of
PR-A TG mice. Both animal models showed excessive lateral branching in virgin
mammary gland, loss in basement membrane integrity, characteristics commonly
associated with transformed cells. Similar to the mammary epithelial cells of
PR-A TG mice, the gland of adult MTA1-TG mice contained some very thick ducts
resembling those seen in early pregnancy. Histological analysis revealed the
glands of MTA1 transgenic mice contained ducts composed of multilayered
luminal cells, in contrast to the monolayer associated with the normal ducts.
This phenotype was also observed in PR-A transgenic mice
(Shyamala et al., 2000
).
Furthermore, in the aberrant mammary epithelial structures in PR-A TG mice,
there is an increase in cyclin D1 expression accompanied by an increase in
cell proliferation (Chou et al.,
2003
). Therefore, it is likely that there is an increased
responsiveness to progesterone in MTA1-TG mice due to the increase in total PR
levels and that regulated growth may require the coordinated actions of PR-A
and PR-B. Ligand-induced ER is also likely to be disrupted by the
overexpression of MTA1. Together, these observations suggest that increased
ductal growth and extensive ductal branching in MTA1-TG mice result from
alterations in the ratios of PR isoforms.
We have demonstrated that MTA1 overexpression in the mammary glands of
pregnant female mice results in a reduced density of alveoli, a defect that is
a consequence of reduced ductal and alveolar epithelial cell proliferation. It
is possible that this phenotype was caused by a decreased PR-B level and
downregulation of cyclin D1 in pregnant MTA1-TG mice. These results are
consistent with those from a recent study showing that the selective
activation of PR-A in PR-B knockout mice caused impaired
progesterone-dependent ductal branching and alveolar morphogenesis during
pregnancy (Mulac-Jericevic et al.,
2003). Thus, upregualtion of PR-A and downregulation of PR-B in
MTA1-TG mammary gland may partially account for the lack of hormonal
dependency for growth in the virgin gland and for the delayed and retarded
development of alveolar-lobular structures during pregnancy.
We have demonstrated that mammary glands of the MTA1-transgenic mice show a delay in involution. Although the mammary glands of the MTA1-TG mice eventually undergo involution, it appears that fewer epithelial cells are lost than in wild-type regressed mammary glands. Delayed involution seen in MTA1-TG mice correspond with a delay in the onset of apoptosis and upregulation of anti-apoptotic molecule Bcl-XL, a target of PR-A.
We demonstrate for the first time that MTA1 play a role in tumorigenesis of
the mammary gland in an MMTV-LTR driven mouse model. Histological analysis of
the mammary tumors showed two adenocarcinoma and three lymphomas. In addition,
30% of transgenic mice developed hyperplastic nodules in the mammary gland.
This observation raises the possibility that the presence of the MTA1
transgene in mammary glands may result in the retention of epithelial
structures, particularly in uni- and multiparous mice, which could lead to the
development of hyperplasia and tumors over time. The fact that MTA1
overexpression upregulate PR-A isoform in the mammary gland could explain in
part the mechanism of tumor formation in MTA1 transgenic mice. These finding
are consistent with previous studies indicating that overexpression of PR-A in
PR-positive tumors may be associated with a more aggressive state. Although
the ratios of PR-A and PR-B appear to be equivalent in the normal mammary
gland, a subset of PR invasive tumors show an imbalance of PR-A and PR-B in
favor of PR-A (Mote et al.,
2001; Mote et al.,
2002
; Graham et al.,
1995
). MTA1 overexpression in human breast cancer cells also
promotes an aggressive phenotype to the cells and induces tumorigenicity in
nude mice (Mazumdar et al.,
2001
) (R.B.-Y. and R.K., unpublished). In addition, the ratio of
PR isoforms was also deregulated in MTA1 overexpressing breast cancer cells.
The fact that cyclin D1 was also upregulated in MTA1-deregulate breast cancer
cells as well as in virgin transgenic mice as well as MTA1-TG tumors suggested
that MTA1 is not a universal co-repressor and that cyclin D1 upregulation
could also contribute to tumorigenesis in mammary gland. It is interesting to
note that co-repressors and co-activators (apparently molecules with opposite
functions) could be found in the same complex because of a highly dynamic
nature of the target gene chromatin
(Perissi et al.,
2004
). In this context, as MTA1 has been shown to interact
with co-activators (Mishra et al.,
2003
; Talukder et al.,
2003
), it is possible that MTA1 may influence gene expression by
multiple mechanisms.
The observation that Bcl-XL was upregulated in MTA1-TG induced
breast tumors is important as it raises the possibility of involvement of
Bcl-XL in to the formation of hyperplastic nodules and breast
tumors in MTA1-TG mice. Indeed, overexpression of the anti-apoptotic protein
Bcl-XL has been implicated in the development, progression and
drug-resistance in tumors (Strasser et
al., 1997). Furthermore, Bcl-XL also plays a crucial
role in protecting cells from DNA damage, regardless of whether or not they
have mutations in p53 pathway (Deverman et
al., 2002
; Klocke et al.,
2002
; Maclean et al.,
2003
), and Bcl-XL expression in tumors is also
considered a good predictor of response to therapy and prognosis
(Sjostrom et al., 2002
;
Vilenchik et al., 2002
). In
addition, Bcl-XL upregulation is widely associated with a higher
tumor grade and increased number of nodal metastases, and, hence, implicated
as an inhibitor of apoptosis during later stages of the disease
(Olopade et al., 1997
).
Together, these findings establish that MTA1 plays an important role in
mammary gland development and tumorigenesis.
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ACKNOWLEDGMENTS |
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