HEREGULIN (GP30) EXPRESSION AND DRUG RESISTANCE

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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.