Breast Disease - Volume 11, issue 1

Authors: Yarden, Yosef

Article Type: Introduction

DOI: 10.3233/BD-1999-11101

Citation: Breast Disease, vol. 11, no. 1, pp. 1-3, 1999

Authors: Zwick, Esther | Wallasch, Christian | Ullrich, Axel

Article Type: Research Article

Abstract: The receptor tyrosine kinase HER2 and its rat homologue neu were independently identified as close relatives of erbB, the gene encoding the epidermal growth factor receptor (EGFR). Genomic analysis of primary tumors revealed HER2 gene amplification and overexpression in breast and ovarian adenocarcinomas and demonstrated strong correlation with poor prognosis. Since its validation as the first human oncogene, HER2 has been intensively investigated as a target for therapeutic intervention. Nevertheless, it is still poorly understood how HER2 overexpression and enhanced cellular signaling contributes to the development of human cancer. Here we summarize the signaling characteristics of HER2 in regard to …its function in tumorigenesis and address recent advances towards the pharmacological intervention in HER2 signaling and anti-cancer therapy Show more

DOI: 10.3233/BD-1999-11102

Citation: Breast Disease, vol. 11, no. 1, pp. 7-18, 1999

Authors: Lacenere, Christopher J. | Sternberg, Paul W.

Article Type: Research Article

Abstract: Mammals contain four members (HER1/EGFR, HER2/Neu, HER3, and HER4) of the epidermal growth factor receptor (EGFR) family, which transduce extracellular signals by EGF family peptide growth factors. Upon binding of ligand with receptor, dimerization and auto-phosphorylation of the receptor results in a cascade of events which transmit signal from the cell surface to the nucleus. Amplification and/or uncontrolled signaling of these receptors is associated with many cancers. 10 to 34% of human breast cancers are associated with amplification or overexpression of the HER2/neu oncogene, an EGFR homolog [1]. Signaling from the EGFR plays a critical role in the development of …many organisms including the nematode Caenorhabditis elegans and the fruitfly Drosophila melanogaster, each of which contain a single EGFR homolog. The powerful genetic techniques offered by these organisms has allowed new components of the EGFR signal transduction pathway to be identified as well as lending insight into the basis of tissue specificity of signaling Show more

DOI: 10.3233/BD-1999-11103

Citation: Breast Disease, vol. 11, no. 1, pp. 19-30, 1999

Authors: Alroy, Iris | Yarden, Yosef

Article Type: Research Article

Abstract: HER2/ErbB-2 belongs to a family of four receptors that bind growth factors as dimers and transmit cellular signals. The ErbB-2 signaling unit shares functional characteristics with other modules whose function is essential for morphogenesis of epithelial organs, including the mammary gland. However, unlike other receptors, ErbB-2 binds no known growth factor ligand with high affinity, and its oncogenic potential is exceptionally high. Biochemical and genetic lines of evidence imply that ErbB-2 is a unique receptor: by serving as a preferred heterodimeric partner of the other ErbB receptors, it enhances and prolongs cell-to-cell signals. ErbB-2-containing heterodimers are long-lived and their signals …are relatively potent because the rate of ligand dissociation is decelerated by ErbB-2, and their rate of endocytosis is relatively slow. Apparently, all ErbB ligands are bivalent molecules, whose low affinity site prefers ErbB-2. Hence, overexpression of ErbB-2 in epithelial tumor cells biases formation of heterodimers, leading to enhanced responsiveness to stromal growth factors and, eventually, to oncogenic transformation. Consequently, removal of ErbB-2 from the cell surface or inhibition of its intrinsic enzymatic activity may reduce oncogenicity. Indeed, anti-ErbB-2 antibodies that can effectively internalize the oncoprotein are therapeutically beneficial. We conclude that ErbB-2 developed as a master regulator of a signaling network essential for normal physiology. However, ErbB-2 opportunistically is exploited by oncogenic mechanisms. This understanding may prove useful for developing clinical strategies to inhibit ErbB-mediated cancer. Show more

DOI: 10.3233/BD-1999-11104

Citation: Breast Disease, vol. 11, no. 1, pp. 31-48, 1999

Authors: Neckers, Len

Article Type: Research Article

Abstract: Several natural product antibiotics, including herbimycin, geldanamycin, and radicicol, bind to an amino terminal nucleotide binding pocket in the heat shock protein Hsp90. Drug binding alters the conformation of Hsp90 and interferes with its ability to chaperone a distinct group of "client" proteins, including a number of transmembrane and soluble tyrosine and serine/threonine kinases. Prominent among the kinases dependent on Hsp90 is the ErbB family member HER2, which is frequently overexpressed in adenocarcinoma and is associated with a poor prognosis and resistance to chemotherapy. Disruption of Hsp90 function promotes the proteasome-dependent and ubiquitin-mediated degradation of HER2, making small molecule chaperone …antagonists exciting candidates for clinical development. Show more

DOI: 10.3233/BD-1999-11105

Citation: Breast Disease, vol. 11, no. 1, pp. 49-59, 1999

Authors: Bacus, Sarah S. | Gudkov, Andrei V. | Esteva, Francisco J. | Yarden, Yosef

Article Type: Research Article

Abstract: Amplification and overexpression of the Her2/neu (c-erbB-2) growth factor receptor occurs in ~ 25% of early stage breast cancers. HER2/neu has been established as an important prognostic factor in early stage breast cancer in large patient populations and has been associated with shorter overall and disease free survival. New data are emerging to suggest that HER2/neu may be useful not only as a prognostic factor but also as a predictive marker for response to chemotherapeutics, anti-estrogens, and therapeutic regimens using anti-HER2/neu monoclonal antibodies. However, little is known of how other erbB receptors tyrosine kinases affect breast cancer biological behavior and response …to therapy. In this review, we highlight recent data on Her2/neu as a prognostic and predictive marker of response to therapy, as well as how the other receptors of the erbB family affect the biological behavior of breast cancer. Show more

DOI: 10.3233/BD-1999-11106

Citation: Breast Disease, vol. 11, no. 1, pp. 63-75, 1999

Authors: Dressler, Lynn G. | Thor, Ann D.

Article Type: Research Article

Abstract: HER2 measurement holds great promise in predicting response to a variety of systemic therapies an exciting step forward in the management of breast cancer patients. The enthusiasm surrounding the clinical importance of HER2, however, is tempered by the uncertainty regarding the clinical usefulness and accuracy of the different methodologies currently available to assess HER2 status. In this paper the authors address laboratory and technical issues associated with methods which measure HER2 overexpression or amplification. We also discuss how these issues can influence the clinical utility and routine application of this marker. While a tumor marker may be considered clinically …relevant, it must be proven to be clinically useful. Optimally, this should occur in the setting of a randomized clinical trial, using methods that are reliable, reproducible, and biologically accurate. For HER2 testing to be a useful, routine clinical marker several critical issues need to addressed. These include the determination and validation of the clinical utility of each method to predict response to the different systemic therapies currently associated with HER2. In addition, there is need to set standards for assay performance and interpretation of assay results, based on criteria that are clinically validated. Show more

Keywords: HER2neu, breast cancer, chemotherapy, tumor markers, standardization, immunohistochemistry, fluorescence in-situ hybridization, erbB-2,

DOI: 10.3233/BD-1999-11107

Citation: Breast Disease, vol. 11, no. 1, pp. 77-87, 1999

Authors: Paik, Soonmyung | Liu, Edison T.

Article Type: Research Article

DOI: 10.3233/BD-1999-11108

Citation: Breast Disease, vol. 11, no. 1, pp. 91-102, 1999

Authors: Carter, Paul | Fendly, Brian M. | Lewis, Gail D. | Sliwkowski, Mark X.

Article Type: Research Article

DOI: 10.3233/BD-1999-11109

Citation: Breast Disease, vol. 11, no. 1, pp. 103-111, 1999

Authors: Krauss, W.C. | Park, J.W. | Kirpotin, D.B. | Hong, K. | Benz, C.C.

Article Type: Research Article

Abstract: Targeting HER2(ErbB-2/neu) overexpressing tumor cells to selectively deliver anticancer agents and thereby reduce host toxicity represents a rational and emerging strategy for the treatment of breast and other epithelial cancers. The extracellular domain of the HER2 receptor tyrosine kinase is readily accessible to systemically administered antibody-based therapeutics, including growth-inhibiting monclonals such as rhuMAbHER2 (trastuzmab/Herceptin©) as well as anti-HER2 immunotoxins, antibody-dependent enzyme prodrug therapy (ADEPT), and immune cell recruiting bispecific antibodies. In addition to summarizing recent advances in these antibody-based strategies, this review focuses on preclinical advances in the development of anti-HER2 immunoliposomes (ILs) as a platform technology for targeted drug …delivery. Extensive in vitro and in vivo testing including efficacy and tumor uptake studies in multiple human tumor xenograft models now provide conclusive evidence for the superior therapeutic efficacy of anti-HER2 ILs-doxorubicin (dox) over free dox or liposomal (Ls)-dox, and even over combinations of dox and Ls-dox with rhuMAbHER2. As anti-HER2 ILs-dox approaches clinical testing in patients with advanced HER2 overexpressing breast cancer, future applications of this novel targeting strategy will also broaden to include intracellular delivery of other anticancer agents as well as therapeutic nucleic acids (oligonucleotides, genes). Show more

DOI: 10.3233/BD-1999-11110

Citation: Breast Disease, vol. 11, no. 1, pp. 113-124, 1999