Project Details

Description

Hormones are involved in a third of all cancers in the United States.
Estrogens in particular have been implicated in cancers of the breast and
of the female genital tract. Diethylstilbestrol (DES), a synthetic
estrogen strongly linked to human cancer, can induce cancer in 100% of
hamsters within six months. There is evidence to suggest that estrogens
have a tumor promoting activity. In addition, estrogens may also
participate in tumor initiation. Here, it is proposed to initiate a
rigorous examination of the possibility that metabolites of estrogens can
elevate background mutagenesis by one or more pathways. The following
specific questions concerning the mutagenic potential of estrogens, using
a reactive metabolite of DES as the model, will be addressed in this
project. (1) Is diethylstilbestrol-4',4"-quinone (DES Q) mutagenic
through a direct covalent or non-covalent interaction with DNA? (2) If it
is mutagenic, (a) which DNA base is the most frequent mutational target?
(b) what is the mutational specificity and which of the known genetic
modulators of mutagenesis affect mutagenesis by DES Q? (c) does the
mutagenic activity correlate with DNA damage at the level of nucleotide
sequence? (3) If it is not mutagenic, does DNA damage occur without
leading to significant mutagenic enhancement? The experimental strategy
for detecting mutagenesis consists of in vitro adduction of model DNA
genomes, their replication in Escherichia coli or in cultured human host
cells, identification and sequence-level characterization of any
mutations in marker genes. DNA damage by DES 0 will be assessed by
covalent binding of radioactive estrogen to DNA, by the post-labeling
method, by methods aimed at detecting cryptic damage, as well as by
current molecular methods for mapping damage sites at the sequence level.
Mutagenic potential of the non-covalent interactions DES Q with DNA will
be assessed in an experimental system in which DNA will be replicated in
vitro in the presence of DES Q, followed by transfection of the
replicated DNA to evaluate mutagenic consequences.Description
StatusFinished
Effective start/end date8/18/927/31/96

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $95,664.00

ASJC

  • Medicine(all)

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