HEREGULIN (GP30) EXPRESSION AND DRUG RESISTANCE

Project: Research project

Project Details

Description

The growth of cancer cells depends on small proteins, termed growth
factors, that bind to and activate their respective receptors. In breast
cancer one of these receptors is the erbB-2 oncogene product. Numerous
studies have, in fact, indicated an important role for erbB-2 over-
expression in breast cancer, as it is correlated with poor prognosis.
However, over-expression by itself cannot account for an increased
invasive potential, since the infiltrating component is often negative.
Recently, we have cloned a putative erbB-2 receptor activator
(gp3O/heregulin), thought to be a ligand for erbB-2. It now appears that
activation of erbB-2 is mediated through the erbB-4 receptor, since we
have recently shown that gp30/heregulin can activate erbB-4 as well as
erbB-2. How cross-talk between these two receptors occurs is not yet
understood. Nevertheless, it is extremely important to determine the
mechanistic aspects of the erbB-2I4/gp3o/heregulln interaction. This could
provide important insight into the mechanism of transition from in-situ to
invasive breast cancer. Furthermore, our preliminary data indicate that
constitutive production of gp30/heregulin, by transfected ER positive MCF-
7 cells, not only induces constitutive erbB-2/4 activation, but also, and
more importantly, an estrogen-independent and anti-estrogen resistante
phenotype, in vitro and in vivo. In addition, presumably by activation of
Topoisomerase II, these cells become exquisitely sensitive to doxorubicin
and VP-16. Therefore, it is important to define the role of
gp30/heregulin expression both in breast cancer progression and in drug
resistance/sensitivity.

We will determine: 1) the relevance of gp3O/heregulin expression, 2) the
significance of erbB-2/erbB-4 gp3O co-expression and, 3) erbB-2/erbB-4 and
gp30 expression, as they relate to prognostic and therapeutic endpoints.
We will use two different groups of specimens. One group will include
specimens from node negative breast cancer patients (before treatment)
including specimens from patients with and without known recurrences. The
second group of specimens will embody a collection of tumor specimens,
consisting of primary and metastatic breast cancer specimens, at varying
stages of progression. The studies will be performed using paraffin-
embedded specimens. For the detection of gp30/heregulin we will utilize a
variety of techniques, that have been recently developed in our
laboratory, including immunohistochemistry, in situ hybridization and RT-
PCR. Receptor expression will be determined by immunohistochemistry. We
believe that our results will provide critical information for
understanding the mechanism and predicting the likelihood of tumor
progression. We will also determine the relationship between expression of
gp30/heregulin, erbB-2/4 and increased sensitivity to doxorubicin/
resistance to tamoxifen in breast cancer specimens. This information
would assist in making therapeutic decisions regarding hormonal and
chemotherapy. This could also form the basis for clinical trials using
doxorubicin in combination with certain biological agents, related to
gp30/heregulin or erbB-2/4 receptors, to improve response to cytotoxic
therapy.
StatusFinished
Effective start/end date6/1/951/31/98

ASJC

  • Medicine(all)