DESCRIPTION (provided by applicant): The etiology of endometrial cancer is
relatively well understood. Estrogen stimulation of the endometrium without the
modulatory effects of progestins is the major cause. Estrogen replacement
therapy (ERT) in menopause and obesity are the principal risk factors. The
effect of the latter is probably due to the association between postmenopausal
obesity and circulating bioavailable estrogen levels. Oral contraceptives and
pregnancy, both of which deliver estrogen stimulation to the endometrium but
with the continuous modulatory influence of progestins, are associated with
reduction in risk. Combination hormone replacement therapy in which a progestin
is added to estrogen for all or part of the monthly cycle results in no
increase in endometrial cancer risk over that of a non-user of hormone
replacement. Despite the fact that ERT and obesity are the major risk factors,
only a small proportion of women using ERT or even with extreme obesity will
develop endometrial cancer. It would be important from a public health as well
as from a mechanistic view to be able to predict which women those will be. We
propose to evaluate a series of eight candidate genes (CYP17, CYP19, HSD17B1,
ER, CYP1A1, CYP1B1, COMT andPR) in the estrogen biosynthesis, transactivation
and metabolism pathways to determine if the effects of these risk factors might
be mediated or modified by genetic variability. We will evaluate this question
in the context of a prospective epidemiologic study of 133,000 female
California teachers (the California Teachers Study) using a nested case-control
design. We will also examine in detail the possible impact of phytoestrogens on
endometrial cancer risk reduction in conjunction with HRT, obesity and the
eight candidate genes under evaluation.
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