Inhibition of mammary gland involution is associated with transforming
growth factor alpha but not c-myc-induced tumorigenesis in transgenic mice
Summary
Deregulated expression of transforming growth factor alpha (TGF-alpha) or c-myc has been
implicated in the genesis of human breast cancer. To better characterize the role of these
molecules in this disease, we generated transgenic mice that express TGF-alpha or c-myc
under control of the mouse whey acidic protein (WAP) promoter. We then compared the
resulting mammary gland neoplasia in these mice and in previously described mice
expressing a metallothionein-driven TGF-alpha transgene. Nonvirgin female mice in all
transgenic lineages developed mammary tumors with 100% incidence but variable latency.
Among TGF-alpha lines, mean survival time correlated with the level of transgene
expression, and the average life spans of high-expressing WAP-TGF-alpha and WAP-c-myc mice
were similarly reduced. The majority of TGF-alpha-induced tumors were relatively
well-differentiated adenomas and adenocarcinomas; in contrast, WAP-c-myc tumors were
poorly differentiated, solid carcinomas with a minority of adenocarcinomas. Most TGF-alpha
and all c-myc-induced tumors were transplantable, but lung metastases were infrequently
observed in all transgenic lines. WAP-TGF-alpha-induced tumors, in marked contrast to
those induced by WAP-c-myc, displayed frequent induction of cyclin D1 mRNA, suggesting
that expression of this gene may complement that of TGF-alpha during mammary tumor
development. Expression of TGF-alpha also induced precocious development of pregnant
glands and delayed or inhibited mammary involution. As a result, multiparious MT-TGF-alpha
and especially WAP-TGF-alpha females accumulated large numbers of hyperplastic alveolar
nodules that resembled the more differentiated TGF-alpha-induced tumors. Finally,
coexpression of WAP-c-myc and WAP-TGF-alpha transgenes markedly decreased tumor latency,
increased tumor growth, and even induced mammary tumors in virgin female and male mice.
These findings provide further evidence for the importance of deregulated TGF-alpha
expression in multistage carcinogenesis, and they suggest that in the mammary gland the
mechanism of TGF-alpha-induced transformation may depend on postlactational survival of
differentiated epithelium. They also provide evidence of a potent tumorigenic
collaboration between TGF-alpha and c-myc in mammary epithelium.
Citations
Inhibition of mammary gland involution is associated with transforming growth factor alpha
but not c-myc-induced tumorigenesis in transgenic mice. Sandgren EP; Schroeder JA; Qui TH;
Palmiter RD; Brinster RL; Lee DC. Cancer Res 1995, 55:3915-3927.
Background
Transgene
A TGF-alpha cDNA was inserted into the Asp718 site within the first exon of a 7kb mouse
WAP gene.
mouse strain
The transgene was introduced into a FVB/N background
Mammary development
Gene expression
Mechanistic implications
key words
Submitted
contributed March 1996
last update: June 1998