Biology Reference
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Previously we had shown that short-term sustained exposure to 100 µg of estra-
diol resulted in pregnancy levels of estradiol in circulation [19,29]. We further
showed that a pregnancy level of estradiol alone or a combination of estradiol and
progesterone was highly effective in inducing refractoriness to chemical carcino-
gen-induced rat mammary carcinogenesis. Similarly to the protection observed in
rats by a pregnancy level of estradiol, activated Her-2/neu mice are also rendered
refractory to mammary cancer development by short-term hormone treatments.
These studies illustrate two of the major paradoxes of the role of hormones
in mammary tumorigenesis. On the one hand, a short duration of estrogen and
progesterone or estrogen alone imparts a protective effect on tumor development.
On the other hand, continuing the same dose of hormones for a prolonged pe-
riod strongly stimulates the development of tumors in this same system as well as
in other mouse models [5,18,30]. This same result has been reported in the rat
mammary tumor system [31]. Different mechanisms underlying the protective
effects have been proposed by several investigators. Sivaraman and colleagues and
Ginger and colleagues [21,32,33] emphasize the induction of a different devel-
opmental fate as a consequence of hormone exposure. Thordarson and colleagues
have argued for a systemic effect involving the downregulation of pituitary hor-
mones [24,34,35]. In either event, one would have to conclude that continuing
exposure to hormones overrides these mechanisms. Mechanistically, the basis for
this override is not clear.
The second paradox is that by either exposing the mammary gland to a short
duration of hormones or blocking the same hormone pathway (for example by
exposure to tamoxifen) a similar result is generated, namely a decrease in tumori-
genic potential. However, the cellular pathways perturbed by the two treatments
might be entirely different because tamoxifen-treated outgrowths do not show the
presence of hyperplasias that occur in the hormone-treated outgrowths.
In summary, these studies provide a further rationale for considering the
use of short-term hormone exposure as a preventive modality, particularly in
high-risk individuals. Despite the extensive documentation of the preventive
potential of early full-term pregnancy and its mimicry by estrogen and pro-
gesterone, there is great resistance to the use of these hormones as a preven-
tive modality. In part, the resistance is due to the overwhelming data showing
that prolonged exposure to estradiol and progesterone increases the risk for
breast cancer [36]. This resistance might be mitigated by recent data indicat-
ing that hormone replacement therapy with estrogen alone does not increase
the risk for breast cancer [37]. Perhaps this resistance will be overcome once
the mechanisms underlying the preventive effects of specific hormone combi-
nations and duration of exposure are understood.
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