MAPPING GENETIC SUPPRESSORS OF EPIGENETIC CARCINOGENESIS

Project Details

Description

Our recent findings have generated a new paradigm for nonmutagenic
mammary carcinogenesis. We demonstrated that the activating Hras1
mutations found in NMU-induced tumors arise as background mutations
within cells of the developing gland, and that NMU enhanced the
phenotypic penetrance of these mutations by initiating alterations in
DNA conformation. We further identified a cell-type-specific, DNA
structure within the Hras1 promoter of normal rat mammary cells(RMCs)
in vivo. The structure has characteristics of H-form DNA and includes
a
putative ets transcription factor binding site. Our results further
demonstrated that depending upon hormonal status of the animals, RMCs
can switch between states where the structural feature is present or
absent from the Hras1 promoter. For this reason, we call this DNA
structure a Conformation Toggle Switch(CS). In the Fischer 344(F344)
and Sprague-Dawley(SD) strains, which are sensitive to mammary
carcinogenesis, a carcinogenic dose of NMU initiated the loss of this
structure from the Hras1 promoter of RMCs. While the Hras1 CS was
restored in normal RMCs by 120 days after exposure, its loss was
irreversible in cells that gave rise to tumors. By contrast, the same
exposure to induce CS disruption in Copenhagen(Cop) rats, which are
highly resistant to mammary carcinogenesis. NMU also failed to promote
the outgrowth of pre-existing Hras1 mutants present in the mammary
epithelium of resistant Cop rats. Moreover, NMU-induced disruption of
the CS in sensitive rats was inhibited by a diet supplemented with a
chemopreventive dose of high selenium garlic. Together our results
suggest that NMU-induced alterations in DNA conformation promote the
outgrowth of pre-existing mutants by irreversibly deregulating
expression of Hras1 and other ets-responsive genes, thereby increasing
the phenotypic penetrance of the conditional Hras1 oncomutations.
Phenotypic analysis of resistant(F344 khi Cop)F1 progeny further
indicated that the suppression of CS disruption was medicated by one or
more dominant suppressors expressed in RMCs of Cop rats. Together our
findings indicated that these genetic suppressors of CS disruption are
putative tumor suppressor genes. The overall goal of this proposal is
to use genetic linkage analysis to map this novel suppressor(s) of
mammary carcinogenesis on the rat genome in preparation for positional
cloning and application to studies of human breast cancer risk, early
detection and prevention.
StatusFinished
Effective start/end date4/1/981/31/04

Funding

  • National Cancer Institute: $338,149.00
  • National Cancer Institute
  • National Cancer Institute: $348,296.00
  • National Cancer Institute: $403,580.00
  • National Cancer Institute

ASJC

  • Genetics
  • Molecular Biology
  • Cancer Research

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