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Abstract: Mammary hyperplasias, dysplasias and tumors have been described
in many strains of transgenic mice. Many of the transgenes produce characteristic
disturbances of growth, development and neoplasia. The disturbances can
now be classified into groups. A classification of transgenic tumors and
an atlas illustrating some characteristic examples of common morphological
changes in transgenic mammary tissues is provided.
Abstract: Activation of the c-Src tyrosine kinase has been implicated
as an important step in the induction of mammary tumors in both mice and
humans. To directly assess the effect of mammary gland-specific expression
of activated c-Src, we established transgenic mice that carry a constitutively
activated form of c-src under transcriptional control of the murine mammary
tumor virus long terminal repeat. Female mice derived from several independent
transgenic lines lactate poorly as a consequence of an impairment in normal
mammary epithelial development. In addition to this lactation defect, female
mice frequently develop mammary epithelial hyperplasias, which occasionally
progress to frank neoplasias. Taken together, these observations suggest
that expression of activated c-Src in the mammary epithelium of transgenic
mice is not sufficient for induction of mammary tumors.
Abstract: 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.
Abstract: Receptor tyrosine kinases are important in cell signal transduction
and proliferation. Abnormal expression of tyrosine kinases often leads to
malignant transformation. C-met is a tyrosine kinase receptor and its ligand
is hepatocyte growth factor (HGF). HGF/c-met plays diverse role in regulation
of cell growth, shape and movement. Constitutively activated met, such as
tpr-met, is a potent oncogene in vitro, but its carcinogenic role in vivo
remains unclear. Our study demonstrates that expression of tpr-met leads
to development of mammary tumors and other malignancies in transgenic mice,
and suggests that deregulated met expression may be involved in mammary
carcinogenesis.
Abstract
Platelets, essential for vascular integrity and hemostasis, fragment from
polyploid megakaryocytes, characterized by their endomitotic cell cycle.
We studied the influence of overexpression of c-myc oncogene on megakaryopoiesis
and endomitosis in vivo, using transgenic mice carrying c-myc fused to the
estrogen receptor under the control of the platelet factor 4 (PF4) megakaryocyte-specific
promoter. The rationale behind this strategy was to obtain controlled overexpression
of an active c-Myc, depending on the estrogen level in the mouse circulation.
Analysis of these transgenic mice revealed that the bone marrow of female
transgenic mice of estrogen-injected male transgenic mice, but not of age-matched
transgenic males nor nontransgenic females, contained frequent immature
myeloid cells and an increased number of megakaryocytes. Deregulated expression
of c-Myc shifted the normal ploidy profile of megakaryocytes due to a significant
increase in proliferating megakaryocytes and a decrease in the fraction
of ploidizing cells. These transgenic mice represent a novel in vivo model
for a Myc-induced myeloproliferative disorder which can be controlled.
Abstract: Signal transduction regulation was interrupted in four independent
transgenic mice by expressing the polyomavirus middle T (PyMT) gene, to
affect the growth and development of the prostate gland and other urogenital
tissues. Expression of PyMT was directed to these tissues by a novel, androgen-inducible
expression vector based on the rat C3(1) gene. Epithelial growth disturbances
ranging from tissue hyperplasia, cellular dysplasia to invasive carcinoma
were observed in the ventral and dorsal prostate. Similar abnormalities
were seen in the coagulating gland, epididymis, and vas deferens. The abnormalities
were recognized by histological changes within the ventral and dorsal prostates
were recognized by histologic disorganization, nuclear pleomorphism, increased
mitosis and abnormal ploidy. Transgene transcription was detected in all
affected tissues, demonstrating that the C3(1)-based vector targeted androgen
sensitive urogenital tissues, especially the prostate. Therefore, the expression
of a protein altering signal transduction pathways disrupts urogenital growth
and development..
23. Tulchin, N., F.S. Lee, L. Ornstein, J. Strauchen
and R.D. Cardiff. Immunohistologic c- myc protein in benign breast disease
and cancer. Int. J. Oncology 9:419-425, 1996. (ABSTRACT)(ILLUSTRATIONS)
Abstract The MTV/myc transgenic mouse model has permitted the analysis of
the effects of exogenously introduced myc genes, fused to the murine mammary
tumor virus promoter, on the development of mammary tumors. We have used
a sensitive immunohistochemical method for studying the Myc protein in eleven
mammary tumors from two independent MTV/myc transgenic lines. The tumors
found in these animals included: four large cell adenocarcinomas (LC), two
type A tumors of Dunn, and one mixed type A and C tumor of Dunn, and four
unclassified adenocarcinomas. The highest levels of staining for Myc were
found in the epithelial cell nuclei of mammary tumors; the nuclei in the
transgenic mesenchyme did not contain detectable antigen. Morphologically
normal transgenic epithelium had foci of stained nuclei. No detectable nuclear
Myc stain was found in non-transgenic mammary glands of FVB mice. This work
supports a role of the Myc protein in mammary tumorigenesis and suggests
a correlation between high levels of Myc and histopathology.
24. Muller, W.J., C..L. Arteaga, S.K. Muthuswamy,
P.M. Siegel, M.A. Webster, R.D. Cardiff, K.S. Meise, F. Li, S.A. Halter
and R. Coffey. Synergistic interaction of the Neu protooncogene and TGFa
in the mammary epithelium of transgenic mice. Molecular and Cellular Biology.
16:5726-5736, 1996. (ABSTRACT)(ILLUSTRATIONS)
Abstract
Transgenic mice expressing either the neu proto-oncogene or transforming
growth factor (TGF-a) in the mammary epithelium develop spontaneous focal
mammary tumors that occur after a long latency. Since the epidermal growth
factor receptor (EGFR) and Neu are capable of forming heterodimers that
are responsive to EGFR ligands such as TGF-a, we examined whether coexpression
of TGF-a and Neu in mammary epithelium could cooperate to accelerate the
onset of mammary tumors. To test this hypothesis, we interbred separate
transgenic strains harboring either a mouse mammary tumor virus/TGF-a or
a mouse mammary tumor virus/neu transgene to generate bitransgenic mice
that coexpress TGF-a and neu in the mammary epithelium. Female mice coexpressing
TGF-a and neu developed multifocal mammary tumors which arose after a significantly
shorter latency period than either parental strain alone. The development
of these mammary tumors was correlated with the tyrosine phosphorylation
of Neu and the recruitment of c-Src to the Neu complex. Immunoprecipitation
and immunoblot analysis with EGFR- and Neu-specific antisera, however, failed
to detect physical complexes of these two receptors. Taken together, these
observations suggest that Neu and TGF-a cooperate in mammary tumorigenesis
through a mechanism involving Neu and EGFR transactivation.
25. Cheung, A., Chen, P., Young,
L., Chao, C., Ndoye, A., Kong, A., and Cardiff, R. Angioigenesis and metastasis
in breast tumors. Sixth World Congress for Microcircuation. Monduzzi Eitore
(Bologna) pg 23-26, 1996.
SUMMARY:
High-metastatic potential [Met-1] and low-metastatic potential [Db-7] breast
tumors have been established as an experimental platform for angiogenesis
(intratumoral micorvessel density [MVD]), microcirculation and metastasis
research. With the utilization of computer-assisted intravital microscopy
and histopathology/immuno-histochemistry procedures, it has been revealed
that angiogenesis is a significant variable in the metastatic process. The
tumor microcirculation of Met-1 is complex and heterogeneous, and the internal
micros vessels exhibit tortuous paths. Microvessel tortuosity (measured
as Tortuosity Index [TI]) is a unique intratumoral feature. The TIs (Met-1:
0.4 +0.01/ Db-7: 0.78 +0.02; p<0.0001) are highly significant measurements
and TI for Met-1 correlates with a high MVD (20.2+9.7 microvessels/200x
field & 32.6 +12.9 microvessels/200x field) and a high metastatic rate (12/14)
in the Met-1 high metastatic potential breast tumors, using the low MVD
(7.6+3.7 microvessels/200x field & 13.5+6.2 microvessels/200x field) and
low metastatic rate (2/13) of Db-7 as low-metastatic potential control.
26. Anthony T.W. Cheung, Lawrence
J.T. Young, Peter C.Y. Chen, Chien Y. Chao, Assane Ndoye, Peter A. Barry,
William J. Muller and Robert D. Cardiff. Microcirculation And Metastasis
In A New Mouse Mammary Tumor Model System. Int. J. Oncology. 1997. 11:66-77,
SUMMARY:
Two new metastatic mouse mammary tumor transplant lines have been established
in nude mice. The Met-1 line, with the Polyomavirus Middle T (PyV-MT) transgene,
metastasized with 100% efficiency. The Db-7 line, expressing a PyV-MT transgene
mutated at positions 315 and 322, metastasized with 8.8% efficiency. Histology
and computer-assisted intravital microscopy demonstrated that internal microcirculation
in Met-1 was more complex than Db-7; Met-1 exhibited higher microvessel
density and tortuosity (P<0.0001) . These indices of microvascular complexity
correlated with the higher Met-1 metastatic rate (P<0.0001). These two
transplantable lines will be useful for investigating the complex relationship
between angiogenesis and metastasis.
27. Deckard-Jantapour, K., W.J.
Muller, L. Chodosh, H.P. Gardner, S.T. Marquis, R.J. Coffey and R.D. Cardiff.
Differential expression of the neu transgene in murine mammary tissues.
Int. J. Oncology 1997,11:235-244.
ABSTRACT
The mammary glands of control FVB and mice with MTV-LTR promoted transgenes
were stained using immunohistochemistry to detect neu expression. Neu was
expressed in the terminal end bud of developing mammary glands and during
early pregnancy in FVB mice. Neu was expressed in all tumors from mice with
the neu transgene but not in tumors expressing TGFa or PyV-MT. Neu was also
expressed sporadically in non-neoplastic mammary cells of transgenic neu
mice. However, most mammary cells expressing neu were dysplastic. The differential
expression of the neu transgene should have important implications in the
interpretation of transgenic biology.
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