Estrogen Promotes Mammary Tumor Development in C3(1)/SV40 Large T-Antigen Transgenic Mice: Paradoxical Loss of Estrogen Receptorα Expression during Tumor Progression
2000
Although
several lines of epidemiological evidence suggest that estrogen
exposure influences the incidence of breast cancer development, the
mechanisms by which estrogen may stimulate the formation of breast
cancer remain poorly understood. We have explored how alterations in
estrogen exposure can influence the development of mammary cancer in
the C3(1)/T AG transgenic model, where estrogen levels and
estrogen receptor α (ERα) expression do not appear to modify the
level of transgene expression. The C3(1)/T AG transgene
becomes transcriptionally active in mammary ductal target cells at 3
weeks of age after the estrogen-induced differentiation of the mammary
epithelial anlage to the ductal outgrowth stage. Complete
maturation of the mammary ductal tree, however, is not required for
cancer development because tumors arise in animals where ductal
branching and terminal end bud formation have been prematurely arrested
by ovariectomy. Mammary tumorigenesis in this model is promoted by
increased estrogen exposure with the development of significantly more
mammary intraepithelial neoplastic lesions and carcinomas associated
with accelerated malignant conversion. The promotion of mammary tumors
in this model appears to occur through an estrogen-induced
proliferation and increase in the number of available target cells for
transformation at the terminal ductal lobular units, as has been
postulated to occur in women who receive hormone replacement therapy
and/or by additional molecular mechanisms. We show, for the first time
in a transgenic mouse model, that mammary tumor progression is
associated with the loss of ERα expression, as has been often
observed in human breast cancers with important clinical significance.
Estrogen signaling may, therefore, serve different functions, depending
upon the stage of tumorigenesis. ERβ expression is up-regulated
during tumor progression, although the functional significance of this
remains to be determined.
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