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neu model, the effect of hormones was tested on the developing mammary gland
at 7 to 10 weeks of age. These results suggest that the translation of this approach
to humans is not limited to the young post-pubescent female but can be applied
to the young to middle-aged adult female. Although the emphasis from the hu-
man epidemiology studies has always been on early first pregnancy as a critical
determinant for protection, the use of a specific hormone combination for short
durations might be applicable to a wider age range than previously thought. This
conclusion is in line with experiments in the rat model that show a protective
effect of hormones even after initiation by a chemical carcinogen. Huggins and
colleagues originally reported that estradiol and progesterone given for 30 days,
beginning 15 days after carcinogen administration, inhibited the appearance of
mammary cancers in rats treated with chemical carcinogens [4]. We also dem-
onstrated that protection against mammary carcinogenesis could be achieved by
treatment with physiological levels of estradiol and progesterone for 21 days or
less [21,22]. In the MMTV-activated neu model, 100 µg of estradiol in the Si-
lastic tubing yielded a circulating level of serum estradiol of 98.56 ± 8.37 pg/ml
(SEM) (n = 6) at 21 days after implantation of the tubing. The groups treated
with estradiol plus progesterone yielded similar results (L Rajkumar, unpublished
data).
In support of the idea that the mature gland is responsive to the protective ef-
fects of a short-term exposure to estrogen and progesterone is the observation that
this hormone combination seems to be acting to delay premalignant progression.
The presence of frequent hyperplasia in the hormone-treated gland but the ab-
sence of invasive cancers supports this conclusion. There is some limited informa-
tion in the literature that supports this idea. Reddi and colleagues have presented
data that show the presence of microtumors in the glands of hormone-treated rats
under conditions in which the controls had a high incidence of invasive cancers
[23]. The data presented in the present study would be the first demonstration
of this result in mice. Experiments that test the growth potential of these micro-
tumors or hyperplasias by transplantation into control animals have yet to be
reported. It is evident that there is a point in premalignant progression at which
the cells are no longer susceptible to the preventive effects of this hormone com-
bination. Examination of the tumor incidence curves of mice that were exposed
to hormones at 23 to 25 weeks of age clearly show that the first tumors appeared
with a latency similar to that in control mice. Thereafter, this group behaved simi-
larly to the mice that received the early exposure to hormone.
One of the cellular mechanisms underlying the protective effect involves a
diminution of the proliferative potential of the mammary cells. All experiments
in the p53-null model demonstrated that the proliferative index of the hormone-
treated cells was reduced by 53% to 85% of that of untreated control mammary
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