Project: Research project

Project Details


The growth of cancer cells in general and of breast cancer in particular
depends, in many cases, upon small proteins termed growth factors that will
bind and then activate their growth factor receptors. One of these growth
factor receptors is the erbB-2 receptor which plays an important role in
the prognosis of breast cancer and is expressed at very high levels in
nearly 30% of human breast cancer patients. Our recent discovery of
gp30/heregulin/NDF has allow us to identify a number of related but
distinct biological endpoints which appear responsive to signal
transduction through the erbB-2/4 receptor. These endpoints of growth,
invasiveness, and differentiation have clear implications for the
emergence, maintenance and\or control of malignancy, and represent
established endpoints in the assessment of malignant progression in human
breast cancer. Preliminary studies in vitro have shown that gp3O induces a
biphasic growth effect on cells with erbB-2 over-expression. Strikingly, we
have recently observed that the erbB-2 signalling pathway can be modulated
by estrogen acting through the estrogen receptor (ER). Conversely, we
observed that down regulation of erbB-2 by estrogen can be blocked by gp3O
acting through the erbB-2 receptor. Clearly, mechanistic aspects of the
erbB-2/4/gp3O interaction need to be understood from a therapeutic
standpoint, and may furthermore provide additional insights into treatment
synergy for certain patients, or enhance treatment regimens for a large
number of women. Understanding the mechanism(s) through which these
interactions occur will provide a rational framework with which we examine
the therapeutic relevance of the interaction, and may serve to expose other
therapeutic targets. These mechanisms will be examined initially using in
vitro cell culture and biochemical systems. Ultimately, we hope that these
experiments will facilitate the emergence of erbB-2-targeted therapy. We
have recently determined the protein sequence of gp3O and obtained its full
length cDNA sequence. In addition, we have cloned two additional forms that
are believed to be alternatively spliced molecules. We are currently
expressing these different forms, in order to determine their biological
effects. The availability of gp3O full length cDNA will provide the tools
we need to acquire a better understanding of the mechanism of action of the
erbB-2 oncogene product and the significance of erbBA in breast cancer. The
proposed studies are designed to define the relevance of gp3O in breast
cancer tumor progression. Specifically, we will: l) Study the regulation of
gp3O by hormones, anti-hormones and differentiation factors, 2) determine
if constitutive activation of erbB-2/4 by gp30/heregulin can bypass the
normal estrogen requirement of estrogen responsive breast cancer cells, 3)
define the mechanism by which gp3O induces breast cancer cells to became
hormone independent and to the mechanism of acquiring an hormone resistant
phenotype, 4) determine if disruption of the erbB-2/4 activation can
restore hormone dependence, and 5) identify isolate and clone genes that
are associated with gp3O induction of a more aggressive phenotype. We
believe that results from these in vitro and in vivo studies may provide
new insights into breast cancer diagnosis, prognosis and treatment.
Effective start/end date9/30/948/31/04


  • Medicine(all)