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(Received for publication, September 28, 1995; and in revised form, December 4, 1995) From the
Expression of the activated neu oncogene in transgenic
mice has been associated with both the synchronous (single-step) and
the stochastic (multistep) transformation of the mammary epithelium. To
determine the basis for these conflicting observations, additional
strains of transgenic mice carrying the activated neu oncogene
under the transcriptional control of the mouse mammary tumor virus
promoter/enhancer were produced. Activated neu transgene
expression, as measured by in situ hybridization and
ribonuclease protection assays, resulted in rapid conversion of the
normal mammary epithelium to malignant phenotype in three independent
strains of mice. Expression of the transgene in male mice led to
epithelial hyperplasia of the epididymis and male infertility but not
malignancy. These results indicate that tissue context is an important
parameter in malignant progression and that expression of appropriate
levels of activated neu is sufficient for rapid production of
mammary tumors in transgenic mice.
The neu oncogene was initially isolated from chemically
induced rat neuroblastomas and was shown to encode a 185-kDa
transmembrane protein that bears close homology to epidermal growth
factor receptor(1) . Sequence analyses of cDNA clones isolated
from these neuroblastomas revealed that activation of neu occurred through a single amino acid change in the transmembrane
portion of the protein(2) . In addition, the human homologue of neu oncogene (c-erbB-2) was shown to be amplified and
expressed in many human primary breast
cancers(3, 4, 5) , and its amplification
inversely correlated with patient survival(6, 7) .
Although amplification of neu has been consistently observed
in a large proportion of human primary human breast cancers, other
groups have reported no correlation between amplification status of neu and clinical
prognosis(8, 9, 10, 11) . However,
overexpression rather than mutation of neu may be the primary
mechanism contributing to breast cancer since examination of primary
breast cancer biopsies has yet to reveal comparable activating
mutations(7, 12) . Given the limitations of these
studies, a number of laboratories have turned to the transgenic mouse
to directly assess the oncogenic potential of neu in the
mammary epithelium. Initially, this was accomplished by linking the
mouse mammary tumor virus (MMTV) ( Given the limited number of MMTV/activated neu strains examined and the considerable variation in both the
spatial and temporal expressions among different transgenic strains
bearing identical transgenes(13, 15) , we decided to
produce several other independent transgenic strains carrying
MMTV/activated neu fusion genes. We also altered the temporal
expression of the activated neu product during mammary
epithelial differentiation to establish whether the state of epithelial
differentiation could influence the transforming properties of the
activated neu transgene. These goals were accomplished by
coupling the neu transgene to a truncated version of the MMTV
long terminal repeats (LTR) that is transcriptionally active only after
the induction of pregnancy(16) . Expression of the activated neu oncogene in three independent transgenic strains carrying
either the intact or truncated MMTV/activated neu fusion gene
resulted in the synchronous appearance of multifocal mammary tumors
involving all mammary glands. In situ hybridization with
transgene-specific probes revealed that acquisition of the transformed
phenotype was closely associated with high levels of transgene
expression. These observations support the contention that expression
of activated neu requires few, if any, additional genetic
events to transform the primary epithelial cell.
To identify transgenic progeny,
genomic DNA was extracted from a 1.5-cm tail using the protocol
described by Muller et al.(13) . The nucleic acid
pellet was resuspended in 100 µl of distilled water at an
approximate DNA concentration of 1 µg/ml. Fifteen µl of the DNA
solution was digested with 30 units of BamHI for 90 min. After
gel electrophoresis and Southern blot transfer(19) , the Gene
Screen filters (DuPont NEN) were hybridized with a neu cDNA
probe radiolabeled with [
Western analyses were conducted
as described by Kanner et al.(23) . Briefly, 50 µg
of tumor extract was electrophoresed through 8% sodium dodecyl
sulfate-polyacrylamide gels and then transferred to nitrocellulose and
reacted with 2 µg/ml of neu polyclonal antibody (Ab-3;
Oncogene Sciences, Cambridge, MA). The proteins were visualized using
the enhanced chemiluminescence (ECL) detection system (Amersham Corp.).
Figure 4:
Photomicrographs of hematoxylin and eosin
stained slides. The organization and distribution of mammary cells are
compared in the following: the mammary fat pad of a nontransgenic FVB
mouse control demonstrating well spaced ducts lined by a single layer
of epithelial cells (87
Figure 1:
Structure of the transgenes. A and B, the unshaded region represents sequences
within the pBR322 vector backbone. The striped region corresponds to the MMTV LTR sequences, and the filled region corresponds to an inert fragment derived from the original PA9
clone (17) . The boundaries of the activated neu cDNA
are shown by the appropriate arrows. The transgenic strains
generated with each of these constructs are shown above the plasmid diagrams. Relevant restriction endonuclease sites are
also identified in the figure.
The tissue specificity of transgene
expression for female and male transgene carriers derived from the
CRNT128 line was assessed by RNase protection assay. Ten µg of
total RNA derived from a variety of organs were hybridized with a
transgene-specific probe. The antisense probe used in this analysis was
directed to the SV40 component of the transgene and yields a
784-nucleotide protected fragment (see Fig. 2B). As shown in Fig. 2, expression of the transgene was detected primarily in
the mammary tumors of female carriers and in mammary tumors, salivary
glands, and epididymides of male carriers. After longer exposure of the
autoradiogram, lower levels of transgene expression were also noted in
a variety of other organs including brain, spleen, thymus, lung, and
kidney (data not shown).
Figure 2:
Tissue specificity of transgene
expression. RNA transcripts corresponding to the pMMTV-neu CRNT transgene in various organs of the CRNT128 transgenic strain.
The antisense probe used in this analysis is derived from the plasmid
pASV (13) and is shown in the map below the autoradiograph. Also shown is the map of the
SV40-derived portion of the transgene. The origins of the sequences in
the transgene and the probe are indicated in the figure. Numbers in the diagrams refer to the SV40 nucleotide
sequence. Expression of the MMTV/neu transgene yields a
784-nucleotide protected fragment and is indicated by the arrow. The female carrier (CRNT439) is a multparous individual
at 135 days of age, and the male carrier (CRNT440) was sacrificed at
220 days of age.
Two other female founder strains (NT163 and
CRNT572) were also assessed for their capacity to express the
transgene. As shown in Table 1, NT163 and CRNT572 female founder
animals expressed high levels of the transgene in the mammary gland. In
contrast to the CRNT128 strain, neither of these founder animals
expressed the transgene in any other tissue examined. The remaining
male NT222 founder animal failed to express the transgene.
To ensure
that these transcripts encoded Neu protein, Western analyses were
conducted on tumor protein extracts using a specific polyclonal
antisera (Ab-3; Oncogene Sciences). As illustrated in Fig. 3, a
prominent 185-kDa species comigrating with the NIH 3T3 cell line
expressing activated neu (SPBNT-5) was observed in tumor
extracts derived from CRNT572 and CRNT128 animals. Lower amounts of Neu
were detected in normal mammary glands derived from nontransgenic FVB
females after longer exposure of the autoradiogram. These results
indicated that the MMTV/activated neu strains express elevated
levels of the activated Neu product in the mammary epithelium.
Figure 3:
MMTV/activated neu tumors express
elevated levels of the activated Neu protein. Western analyses of tumor
extracts (CRNT572, 115 days of age, and CRNT128, 132 days of age) or
normal mammary gland extracts derived from nontransgenic FVB/N female
mouse reacted with a neu-specific antibody (Ab-3, Oncogene
Science). Also included are extracts derived from NIH 3T3 cells
(SPBNT-5) expressing the activated neu product under SV40
transcriptional control and the parental NIH 3T3 cell. The 185-kDa Neu
protein is illustrated by an arrow.
Figure 5:
In situ hybridization of
MMTV/activated neu mammary tissue. A,
transillumination photograph of a section of mammary tissue derived
from a multiparous CRNT128 female (200
Although we were unsuccessful in propagating the CRNT572 strain,
female transgenic progenies were obtained from the CRNT128 founder
animal. These transgene carriers also developed multifocal mammary
tumors that involved the entire mammary epithelium following weaning of
their first litters. Consistent with this histological evaluation,
these tumors grew when transplanted into syngeneic recipients. Both the
rapid kinetics by which these tumors appear and their global
involvement suggest that expression of activated neu in the
mammary gland results in rapid conversion of the epithelium to the
malignant phenotype. Male transgenic carriers derived from the
CRNT128 strain also developed mammary tumors with 100% penetrance,
albeit with delayed kinetics (Table 1). In addition, these males
had bilateral epididymal hypertrophy and were infertile. Consistent
with previous observations (13, 14) , these
epididymides exhibited extensive epithelial hyperplasia (data not
shown).
Here, we present further evidence that mammary gland-specific
expression of the transforming allele of the neu oncogene
results in the induction of multifocal mammary adenocarcinomas. Three
independently derived transgenic lines expressing activated neu eventually developed multifocal adenocarcinomas. Multiple mammary
tumors expressing high levels of the transgene arose synchronously in
both transgenic male and female carriers. Histological evaluation of
tissue adjacent to tumors revealed only a sparse amount of normal
tissue. The normal tissue adjacent to the tumors did not express
activated neu as assessed by in situ hybridization
analyses (Fig. 5B). Both the rapid tumor kinetics and
multifocal tumor phenotype exhibited by these transgenic strains
supports the hypothesis that expression of activated neu leads
to rapid and uniform transformation of the mammary epithelium. Interestingly, two of the founder strains derived by microinjection
of the activated neu construct in which the MMTV LTR was
truncated at the ClaI site (CRNT128 and CRNT572), did not
exhibit mammary epithelial abnormalities until after weaning of their
first litter. While we were not able to assess the levels of transgene
expression in these strains prior to tumor development, previous
experience with transgenic mice bearing a truncated MMTV LTR driving
the expression of the murine int-2 gene indicated that
transgene expression is not detectable in virgin mammary epithelium and
does not commence until the animals have become pregnant(16) .
Consistent with these observations, it has recently been reported that cis-acting sequences that are removed in these truncated LTR
are required for optimal hormonal response by the MMTV LTR
promoter/enhancer(27) . By contrast, transgenic mice possessing
an intact MMTV LTR driving the expression of the activated neu gene express the transgene early in mammary gland development and
exhibit early onset of mammary epithelial abnormalities (NT163; (13) ). Other strains of MMTV/activated neu mice
develop tumors in a stochastic fashion(13, 14) . In
the former report(13) , the stochastic appearance of tumors
correlated with increased expression of activated neu (as
assessed by in situ hybridization) in tumor tissue by
comparison with the adjacent normal mammary epithelium (NK line). By
contrast, Bouchard et al. (14) reported that by
Northern blot analyses, the normal epithelium derived from several
transgenic strains expressed comparable levels of activated neu transcript in adjacent normal and tumor tissue. Although
unpublished observations made by the authors suggested that expression
of activated neu in the normal epithelium could also be
detected at the level of the single cell by in situ hybridization, it was not clear whether quantitative differences
of expression were observed between normal and transformed tissue.
Conceivably, the differences between the observations made here and
elsewhere (13) and those made by Bouchard et al. (14) are simply due to variation in the levels of expression of
the active neu tyrosine kinase activity in the mammary
epithelium of the different MMTV neu strains. Moreover,
Lucchini et al.(28) have recently reported multifocal
mammary tumors arising in transgenic mice carrying an identical
MMTV/activated neu transgene. Direct comparison of the levels
of neu kinase activity in the mammary epithelium of the
stochastic and rapid tumor progression strains should allow this point
to be addressed. The behavior of the activated neu oncogene
in the mammary epithelium contrasts with the observations made by a
number of laboratories with transgenic mice carrying other activated
oncogenes. For example, expression of c-myc, c-fos,
or v-Ha-ras, in a number of tissue types requires the
complementary action of other genes to convert the primary cell to the
malignant
phenotype(17, 29, 30, 31, 32) .
It has been suggested that the rapid tumor progression phenotype
observed in the original TG.NF MMTV/activated neu strain might
be the consequence of the integration site(33) . However, three
additional strains develop similar phenotypes. This strongly implies
that the rapid tumor progression observed is the direct consequence of
elevated expression of activated neu. The potent
tissue-specific transforming activity of activated neu in the
mammary epithelium differs from the observations made with transgenic
mice expressing the unactivated neu allele in the mammary
epithelium(34) . In those studies, focal mammary tumors
appeared next to transgene expressing normal epithelium only after long
onset(34) . Perhaps the level of neu tyrosine kinase
activity in the MMTV/unactivated neu lines is below a critical
threshold required to convert the cell to the malignant phenotype, and
cellular transformation occurs only when this threshold is exceeded.
Consistent with this hypothesis, both in vitro kinase assays
with neu-specific antibodies on protein extracts derived from
the MMTV/unactivated neu tumors demonstrate that the neu-induced tumors express a much higher neu-associated tyrosine kinase activity by comparison with the
adjacent mammary epithelium(34) . The levels of active neu tyrosine kinase may also be important in the genesis of human
breast cancer since a large proportion of human breast tumors express
relatively high level of the Neu protein by comparison with the
adjacent normal mammary epithelium(6, 7) . Expression of the polyoma virus middle T associated tyrosine kinase
in the mammary epithelium also results in the rapid conversion of the
entire mammary epithelium to the malignant phenotype(35) .
Conceivably, the powerful tissue-specific transforming activities of
both the activated neu and polyoma virus middle T oncogene
might be explained by the fact that their tyrosine kinase activities
are refractory to normal cellular regulation. Thus, as a consequence,
these activated oncogenes can constitutively signal cell proliferation.
Whether both of these potent tyrosine kinases signal cellular
proliferation through a common signal transduction pathway in the
mammary epithelium awaits further analyses.
Volume 271,
Number 13,
Issue of March 29, 1996 pp. 7673-7678
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
)promoter/enhancer to a
cDNA encoding the activated neu oncogene and introducing this
fusion gene into the germ line of mice(13) . In one strain of
MMTV/activated neu transgenic mice, the early onset of
transgene expression was initially associated with poor lactation.
Later, tumors involving all mammary glands in every transgenic mouse,
both male and female, appeared synchronously. Histological examination
of these tumors revealed a complete absence of normal mammary
epithelium. Both the simultaneous occurrence and multifocal nature of
these tumors argued that expression of activated neu alone was
sufficient for rapid transformation of the mammary epithelium. By
contrast, another group (14) has reported that in four other
transgenic strains, expression of a similar MMTV/activated neu fusion gene resulted in the stochastic appearance of mammary
tumors. Because these tumors arose next to normal epithelium, which
also expressed the transgene, additional genetic events were thought to
be required for malignant transformation of neu-expressing
cells.
Generation and Identification of Transgenic
Mice
The plasmids pMMTV NT and pASV were constructed as
described previously (13) . To establish the transgenic strains
NT163 and NT222 pMMTV NT DNA was digested with 4 units (each) of SalI and EcoRI per microgram for 90 min. The DNA was
electrophoresed through a 1% agarose gel and purified as described
previously(17) . FVB female mice (Taconic farms, Germantown,
NY) were mated the night before injection with FVB males, and the
pronuclei of fertilized one-cell mouse embryos were injected with one
pl of DNA solution (5 µg/ml). Following microinjection, viable eggs
were washed once in M2 media (18) and transferred to the
oviducts of pseudopregnant Swiss-Webster mice (Taconic Farms). The
CRNT572 and CRNT128 strains were established in a similar manner except
that the pMMTV neu NT DNA was cleaved with 4 units (each) of ClaI and EcoRI.
-P]dCTP by random
priming(20) .
RNA and Protein Analysis
RNA was isolated from
tissues by the procedure of Chirgwin et al. (21) using
a cesium chloride sedimentation gradient. RNA yield was determined by
UV adsorption at 260 nm after dissolving in sterile H
O. RNA
probes were made with the pGEM-based vector pASV (ProMega Biotech,
Madison, WI), and RNase protection assays were conducted using the
procedure described by Melton et al. (22) using 10
µg of total cellular RNA/assay.In Situ Hybridization
Mammary tissue was fixed in
freshly prepared 4% paraformaldehyde/phosphate-buffered saline for 4
hours, embedded, and sectioned following standard
procedures(24) . Deparaffined sections were pretreated and
hybridized with [-S]UTP-labeled sense and
antisense pASV probes as described previously (25) with the
modification that the probes were not degraded. Autoradiography was
performed using standard techniques (26) . All sections were
counterstained using hematoxylin and eosin.
Histological Evaluation
Complete autopsies were
performed, and both gross and microscopic evaluations were conducted.
Tissues were fixed with 4% paraformaldehyde, blocked in paraffin,
sectioned at 4 µm, routinely stained with hematoxylin and eosin,
and examined as indicated in Fig. 4.
) (A); the mammary fat pad of an
activated neu transgenic animal demonstrating a dilated
collecting duct with adjacent areas of dysplastic cystic alveoli and
solid neoplastic alveolar development (NT163, 173 days of age)
(87) (B); the solid neoplastic area of the gland in panel B enlarged to demonstrate dysplastic cells filling the
mammary lobules but without growth through the basement membrane,
thereby fulfilling the criteria of carcinoma in situ (350) (C); and a typical malignant tumor showing
the nuclear pleomorphism and irregular, invasive growth pattern of a
mammary adenocarcinoma found in animals with the activated neu transgene (NT163, 173 days of age) (350) (D).
Generation of MMTV/Activated neu Transgenic Mice and
Tissue Specificity of Expression
To target expression of the
activated neu oncogene to the mammary epithelium, two
different MMTV/activated neu fusion genes were microinjected
into one cell mouse embryo (see Fig. 1). The first construct
contained the complete MMTV LTR (Fig. 1B) which is
expressed during all stages of mammary gland development. The
pregnancy-induced MMTV promoter was constructed by truncating the MMTV
LTR at the ClaI site (Fig. 1A). Truncation of
these LTR sequences is known to affect the temporal pattern of
expression of the transgene during mammary gland
development(16) . However, this recombinant still retains the
hormone-responsive transcriptional sequences required for efficient
expression in the mammary epithelium. Both MMTV/activated neu constructs contain identical cDNAs encoding the activated neu product with the Simian virus 40 (SV40) transcriptional processing
signals located at the 3` end of the transgene. Plasmid sequences were
removed prior to microinjection of one cell mouse embryo with
appropriate restriction endonucleases. Two separate transgenic founder
animals for each construct were established. Two of these (CRNT128 and
CRNT572) were established by introduction of the ClaI-truncated pMMTV neu NT. Two others (NT163 and
NT222) were obtained by microinjection of the pMMTV NT construct
bearing the entire LTR.
Mammary Gland-specific Expression of Activated neu
Induces Multifocal Mammary Adenocarcinomas
The expression of the
activated neu gene in the mammary glands of female transgenic
mice had dramatic consequences. As observed with other MMTV/activated neu strains(13) , the initial phenotype exhibited by
the female NT163 was poor lactation, which resulted in the inability of
the founder animal to nurse its offspring. By 90 days of age, this
animal began to develop mammary tumors that eventually involved the
entire mammary epithelium. By comparison to normal mammary fat pad (Fig. 4A), most of the mammary gland derived from the NT163
founder appeared histologically abnormal, containing areas of
dysplastic and neoplastic epithelium (see Fig. 4, B, C, and D). By contrast, two other female founder
animals (CRNT128 and CRNT572) established by microinjection of the
pregnancy-induced truncated MMTV/activated neu construct (Fig. 1A) were able to nurse their first litter.
However, shortly after the weaning of their initial progeny both
founders also began to develop multifocal mammary tumors (Fig. 5A). Because of the massive tumor involvement, both
founder animals were incapable of nursing further litters. Histological
evaluation of these tumors revealed multiple zones of dysplastic and
overtly malignant tissue throughout the mammary fat pad with only
scattered amounts of residual normal epithelium (Fig. 5A).
) stained with hematoxylin
and eosin. B, sequential section of CRNT128 mammary tissue
hybridized to [-S]UTP labeled antisense
SV40 probe (see Fig. 2) (200
). The tumorous tissue
covered with silver grains is the same mammary duct as in panel
A, and this section is immediately adjacent to that shown in panel A. Note the lack of hybridization over the normal
epithelium (see arrow). C, sequential section of
CRNT128 (200) tissue hybridized to a labeled sense control
probe. No significant hybridization was
observed.
Expression of the Activated neu Is Correlated with Rapid
Tumor Progression
Histological analyses suggested that
expression of the activated neu gene was associated with
widespread transformation of the mammary epithelium. Expression of the
transgene was correlated with malignant transformation by employing in situ hybridization with a transgene-specific probe (see Fig. 2B) on sections of mammary tissue derived from
CRNT128 female founder animal. As shown in Fig. 5A, the
mammary epithelium obtained from CRNT128 contained neoplastic,
dysplastic, and sparse normal epithelium scattered throughout the
mammary fat pad. Hybridization of sequential sections with the
antisense probe resulted in the appearance of dense silver grains over
the abnormal epithelium (see Fig. 5B). By contrast,
hybridization with a sense control probe resulted in only weak
background hybridization (Fig. 5C). Significantly,
little hybridization with the antisense probe was observed over sparse
histologically normal epithelium (see arrow). Similar in
situ hybridization analyses were also conducted with mammary
epithelium derived from the NT163 founder animal, and consistent with
the results illustrated here, the appearance of morphologically
transformed epithelium strictly correlated with elevated expression of
the activated neu transgene (data not shown). Taken together,
these results suggest that expression of the activated neu is
associated with the rapid conversion of the mammary epithelium to the
transformed phenotype.
)
We thank Dr. P. Leder and Dr. R. Weinberg for
providing the plasmids pMMTV neu NT and pASV. We appreciate
the excellent photographic support of Robert Munn.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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J. E. Maglione, D. Moghanaki, L. J. T. Young, C. K. Manner, L. G. Ellies, S. O. Joseph, B. Nicholson, R. D. Cardiff, and C. L. MacLeod Transgenic Polyoma Middle-T Mice Model Premalignant Mammary Disease Cancer Res., November 1, 2001; 61(22): 8298 - 8305. [Abstract] [Full Text] [PDF]
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 D. Dankort, B. Maslikowski, N. Warner, N. Kanno, H. Kim, Z. Wang, M. F. Moran, R. G. Oshima, R. D. Cardiff, and W. J. Muller Grb2 and Shc Adapter Proteins Play Distinct Roles in Neu (ErbB-2)-Induced Mammary Tumorigenesis: Implications for Human Breast Cancer Mol. Cell. Biol., March 1, 2001; 21(5): 1540 - 1551. [Abstract] [Full Text]
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A. E. G. Lenferink, J. F. Simpson, L. K. Shawver, R. J. Coffey, J. T. Forbes, and C. L. Arteaga Blockade of the epidermal growth factor receptor tyrosine kinase suppresses tumorigenesis in MMTV/Neu + MMTV/TGF-alpha bigenic mice PNAS, August 6, 2000; (2000) 160564197. [Abstract] [Full Text]
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R. T. Reilly, M. B. C. Gottlieb, A. M. Ercolini, J.-P. H. Machiels, C. E. Kane, F. I. Okoye, W. J. Muller, K. H. Dixon, and E. M. Jaffee HER-2/neu Is a Tumor Rejection Target in Tolerized HER-2/neu Transgenic Mice Cancer Res., July 1, 2000; 60(13): 3569 - 3576. [Abstract] [Full Text]
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R. J. Lee, C. Albanese, M. Fu, M. D'Amico, B. Lin, G. Watanabe, G. K. Haines III, P. M. Siegel, M.-C. Hung, Y. Yarden, et al. Cyclin D1 Is Required for Transformation by Activated Neu and Is Induced through an E2F-Dependent Signaling Pathway Mol. Cell. Biol., January 15, 2000; 20(2): 672 - 683. [Abstract] [Full Text]
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M. J. Rauh, V. Blackmore, E. R. Andrechek, C. G. Tortorice, R. Daly, V. K.-M. Lai, T. Pawson, R. D. Cardiff, P. M. Siegel, and W. J. Muller Accelerated Mammary Tumor Development in Mutant Polyomavirus Middle T Transgenic Mice Expressing Elevated Levels of Either the Shc or Grb2 Adapter Protein Mol. Cell. Biol., December 1, 1999; 19(12): 8169 - 8179. [Abstract] [Full Text] [PDF]
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R. H. Kim and J. Sodek Transcription of the Bone Sialoprotein Gene Is Stimulated by v-Src Acting through an Inverted CCAAT Box Cancer Res., February 1, 1999; 59(3): 565 - 571. [Abstract] [Full Text] [PDF]
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 K. Boggio, G. Nicoletti, E. Di Carlo, F. Cavallo, L. Landuzzi, C. Melani, M. Giovarelli, I. Rossi, P. Nanni, C. De Giovanni, et al. Interleukin 12-mediated Prevention of Spontaneous Mammary Adenocarcinomas in Two Lines of Her-2/neu Transgenic Mice J. Exp. Med., August 3, 1998; 188(3): 589 - 596. [Abstract] [Full Text] [PDF]
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G. Levkowitz, S. Oved, L. N. Klapper, D. Harari, S. Lavi, M. Sela, and Y. Yarden c-Cbl Is a Suppressor of the Neu Oncogene J. Biol. Chem., November 3, 2000; 275(45): 35532 - 35539. [Abstract] [Full Text] [PDF]
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E. R. Andrechek, W. R. Hardy, P. M. Siegel, M. A. Rudnicki, R. D. Cardiff, and W. J. Muller Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis PNAS, March 28, 2000; 97(7): 3444 - 3449. [Abstract] [Full Text] [PDF]
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A. E. G. Lenferink, J. F. Simpson, L. K. Shawver, R. J. Coffey, J. T. Forbes, and C. L. Arteaga Blockade of the epidermal growth factor receptor tyrosine kinase suppresses tumorigenesis in MMTV/Neu + MMTV/TGF-alpha bigenic mice PNAS, August 15, 2000; 97(17): 9609 - 9614. [Abstract] [Full Text] [PDF]
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