Hormone-Induced Protection of Mammary Tumorigenesisin Genetically Engineered Mouse Models - Genetic Engineering: Recent Developments in Applications - page 282

cells at the steady-state level observed in the mature gland. Interestingly, the abil-
ity of the short-term hormone treatment to stimulate proliferation and differen-
tiation during the expansion period at 2 to 6 weeks after transplantation was not
compromised, because the extent of filling of the fat pad was the same in the two
groups at 6 weeks after transplantation. This suggests that the mechanism for
controlling proliferation in the two states (that is, expanding versus a steady-state
cell population) might be different either at the level of the cell type that is prolif-
erating in the two states or at the molecular level. We have not yet evaluated the
proliferative indices of the hyperplasias in the control and hormone-treated mice
because the original observations that determined the presence of these hyperpla-
sias in the hormone-treated mice were performed on whole mounts of the glands,
and, indeed, the result was surprising to us. However, in the MMTV-activated
neu model, the decrease in proliferative activity was also observed in the tumors
arising in the hormone-treated mice. This decrease was manifested at the cellular
level in a decrease in cyclin D1 expression.
Perhaps the most surprising result is the apparent systemic effect of the hor-
mones. This experiment demonstrated conclusively that the effect of the hor-
mones can be mediated, in part, by changes induced at the systemic level and/
or the mammary stroma. This idea was presented by Thordarson and colleagues
in studies on the carcinogen-induced rat mammary system [24]. Attempts to test
this hypothesis were only partly successful [25]. The results presented here dem-
onstrate conclusively that hormone-induced effects at the systemic level and/or
at the mammary stroma can affect tumorigenesis in the p53-null mammary cells.
Such an effect is not without precedent. Barcellos-Hoff and Ravani demonstrated
that irradiated stroma can alter premalignant progression of a mouse mammary
outgrowth line, COMMA-D [26]. Maffini and colleagues showed that stroma
treated with a chemical carcinogen (N-methyl-N-nitrosourea) can enhance the
progression of rat mammary cells to mammary tumors [27]. Schedin and col-
leagues [28] demonstrated that the extracellular matrix of mammary stroma from
different reproductive states alters mammary epithelial morphogenesis as well as
mammary epithelial growth rate. Specifically, they showed that matrix isolated
from parous stroma delayed glandular morphogenesis. The cellular and molecular
mechanisms underlying the changes systemically or at the mammary stroma are
beginning to be identified. Alterations in both transforming growth factor- β sig-
naling [26] and growth hormone signaling [23,24] have been implicated. Inter-
estingly, we could not demonstrate altered systemic insulin-like growth factor-1
levels in our hormone-treated mice at 4 weeks after hormone removal (D Medina
and A Lee, unpublished data).
Finally, it is apparent that the preventive activity can be induced by a modest
dose of estrogen alone (100 µg) or a combined dose of estrogen and progesterone.