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pathway, either the estrogen receptor or estrogen metabolism [2]. Many risk fac-
tors for breast cancer development involve the hormonal history of the patient,
including early age of menarche, late age of menopause, late age of first pregnancy,
nulliparity, and estrogen/progesterone hormone replacement exposure. Indirectly,
postmenopausal obesity and alcohol consumption are thought to enhance breast
cancer risk through altering estrogen levels [3].
Paradoxically, one of the strongest and extensively documented protective fac-
tors for breast cancer in both humans and rodent models is short-term stimu-
lation with hormone, either by means of an early full-term pregnancy or with
the hormones estrogen and progesterone. The protective properties of estrogen
and progesterone were initially shown in 1962 by Charles Huggins [4] and the
extensive studies in this area have been reviewed [5,6]. Studies over the past 30
years to document and understand the mechanistic basis for this phenomenon
have used the traditional rat and mouse chemical-carcinogen-induced mammary
tumor models. These models use etiological agents that are thought not to be risk
factors in human breast cancer. One of the known risk factors in human breast
cancer is exposure to radiation [7]. Ironically, in the only study done in the rat
where radiation was the initiating agent, hormones were not protective [8]. These
considerations raise the question of the relevance of the traditional models for
understanding the mechanism of the protective effects of hormones.
Over the past 10 years, there have been many new mouse models of mammary
cancer based on the enhanced or deleted expression of specific genes known to
have a role in human breast cancer [9]. One of the best-studied models is dele-
tion of the p53 gene in BALB/c mammary epithelium [10,11]. In this model, the
deletion of p53 gene expression does not perturb the normal growth and differ-
entiation of the mammary epithelium nor its normal dependence on hormones.
However, risk for spontaneous mammary cancer is increased over a 14-month
period, and this risk is enhanced by prolonged stimulation with estrogen and
progesterone, by irradiation, or by chemical carcinogens [10-12]. The cancers that
arise in these mice are locally invasive, exhibit metastases to the lung, and about
20% retain hormone dependence. In addition, the premalignant phenotype mim-
ics that of human ductal carcinoma in situ both morphologically and with respect
to retaining estrogen receptor expression [11]. A study of gene expression profiles
of tumors arising in the p53-null mammary epithelium with a randomly selected
group of stage 1 and 2 human breast cancers found a large number of genes that
were commonly expressed in both sets of tumors [13].
A second and more tumorigenic model is the activated Her-2/neu (murine-
mammary-tumor virus (MMTV)-c-neu) transgenic mouse model [14,15].
HER-2/neu, an abbreviation for human epidermal growth factor receptor-2, is
a proto-oncogene, which when activated by mutation or overexpressed has a role
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