||5P01CA077596-05 Interpret this number
||University Of Pennsylvania
||Molecular Susceptibility to Hormone Induced Cancer
It has long been recognized that female hormones, whether endogenous or
exogenous, can be risk factors for female cancers. The overall objective
of this Program is to better understand the molecular mechanisms for
susceptibility to these hormone-associated cancer. In particular, hormone-
mediated carcinogenesis can be seen as a multi-step process that may
involve genetic regulation of the effectors of hormones, as well as
somatic genetic changes subsequent to hormone exposures. This Program has
mobilized investigators in pharmacoepidemiology, field epidemiology,
genetic epidemiology, endocrinology, pathology, and molecular biology, to
bring their talents to bear on this question, examining the relationships
among hormone exposures, inherited susceptibility, and the somatic genetic
sequelae of these exposures in the etiology of hormone-sensitive female
This Program is composed of three Projects and four Cores. The genetic
modification of hormonal exposures in breast and endometrial
carcinogenesis will be studied in Projects 1 and 2. Each will use a
population-based case-control study design, where hospitalized incident
cases of each disease will be compared to a partially shared set of
controls who will be selected randomly from the community using random
digit dialing. The comparison of these two groups of cases to a group of
community controls without the diseases of interest will be used to
investigate risk factors for these diseases. A population-based case-
control study offers several important advantages over other types of
case-control studies, especially by limiting the possibility of selection
bias, the major disadvantage of a non-population-based case-control study.
Study subjects in both Projects will undergo a common, structured
telephone interview. Particular areas of interest will be hormone
exposures, family history, and reproduction-associated exposures,
especially parity. In addition, cases will have their medical records
reviewed as needed to validate information about their cancer. DNA bio-
samples will also be collected to measures specific candidate
susceptibility genotypes involved in hormone metabolism.
The third Project will complement the population-based etiological studies
by contributing to knowledge about molecular events associated with
reproductive hormonal exposures that later breast cancer susceptibility.
This study will have both an animal component and a human component. The
animal component will use an established rodent model to develop and
evaluate candidate genetic markers that reflect the molecular changes that
occur in the breast as a result of parity. Those biomarkers identified as
being of potential importance will then be evaluated further in human
breast tissue, attempting to understand those parity-associated molecular
changes in breast tissue that alter breast cancer susceptibility. The
results from the human tissue will be analyzed in conjunction with
exposure data obtained using the same questionnaire as that to be
administered in Projects 1 and 2. This information will then be used to
explore the basic molecular mechanisms that underlie the known
epidemiologic associations between hormone-related reproductive events and
breast cancers. The information resulting from this transitional study
will also be useful in the future development of genetic markers, that can
then be evaluated further in studies such as those in Projects 1 and 2.
These three Projects will be supported by four Cores: an Administrative
Core (responsible for coordination), a Hospital Network Core (responsible
for hospital-based activities, including IRB approvals, case
ascertainment, medical record abstraction, and specimen collection), a
Field Core (responsible for identification of control subjects,
recruitment of subjects into the study, questionnaire development, and
administration of interviews), and a Data Management and Biostatistics
Core (responsible for development and maintenance of a subject tracking
system, data entry, data management, and biostatistical analysis). Each of
the four Cores will serve all three of the Projects, in such a way as to
maximize quality and efficiency simultaneously.
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