MITOTIC MODIFIERS OF HORMONE-DEPENDENT BREAST CANCER

Project: Research project

Project Details

Description

Breast cancer is the leading cause of death in women in the United States
and its incidence has rapidly increased over the past decade. This
Program Project focuses on the biologic mechanisms whereby hormones
control cellular proliferation, modulate genotypic and phenotypic
cellular changes, and influence tumor invasiveness and metastasis.
Several innovative new hypotheses arising from recent results in several
of our laboratories will be tested in the studies proposed. To highlight
some of these, we propose that constitutive polyamine synthesis may
initiate an aggressive tumor phenotype; that insulin-like growth factor
binding proteins may modulate tumor cell proliferation; that variant
progesterone receptors may exert negative effects on progestin action;
that neutrophils may serve to create holes in basement membranes allowing
tumor cells to penetrate and invade tissues; and that tumor cells may
develop enhanced estradiol sensitivity upon estrogen deprivation.

The overall goals of the Program Project are to examine the mechanisms
which modify the mitotic, cell proliferative, and metastatic behavior of
breast cancer cells growing in vitro in liquid culture, in vivo in animal
systems and spontaneously in patients. Identification of these
mechanisms should allow targeting of therapy to specific key processes.
The strengths and expertise of the investigators participating in this
Program Project facilitate focus on several key regulatory steps
including polyamine metabolism (Project 1), insulin-like growth factors
and their binding proteins (Project 2), progesterone receptor physiology
and receptor variants (Project 3), factors controlling invasiveness and
metastasis (Project 4), and regulation of responsiveness to estrogens
(Project 5). Experiments address testable hypotheses by directly
examining specific molecular processes, by evaluating cellular changes,
and by examining biologic events such as metastases in animal models.
A full understanding of the hormonal control of mitotic processes will
enable identification of key steps which are bypassed in the process of
evolution to aggressive tumor phenotypes. Data resulting from these
studies should allow selection of several key steps for treatment
intervention. While more complete blockade of aromatase is a current
priority, we expect the proposed studies to identify several other steps,
such as ornithine decarboxylase, as targets for therapeutic intervention.
StatusFinished
Effective start/end date1/1/907/31/98

Funding

  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute
  • National Cancer Institute

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