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Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cells

Oncogene volume 18, pages 6050–6062 (1999)Cite this article

Abstract

The heregulins are a family of ligands with ability to induce phosphorylation of the p185HER-2/neu receptor. Various investigators have reported a variety of responses of mouse and human breast and ovarian cells to this family of ligands including growth stimulation, growth inhibition, apoptosis and induction of differentiation in cells expressing the HER-2/neu receptor. Some of the disparity in the literature has been attributed to variations in the cell lines studied, ligand dose applied, methodologies utilized or model system evaluated (i.e. in vitro or in vivo). To evaluate the effects of heregulin on normal and malignant human breast and ovarian epithelial cells expressing known levels of the HER-2/neu receptor, this report presents the use of several different assays, performed both in vitro and in vivo, in vitro proliferation assays, direct cell counts, clonogenicity under anchorage-dependent and anchorage-independent conditions, as well as the in vivo effects of heregulin on human cells growing in nude mice to address heregulin activity. Using a total of five different biologic assays in nine different cell lines, across two different epithelia and over a one log heregulin dose range, we obtained results that clearly indicate a growth-stimulatory role for this ligand in human breast and ovarian epithelial cells. We find no evidence that heregulin has any growth-inhibitory effects in human epithelial cells. We also quantitated the amount of each member of the type I receptor tyrosine kinase family (RTK I, i.e. HER-1, HER-2, HER-3 and HER-4) in the cell lines employed and correlated this to their respective heregulin responses. These data demonstrate that HER-2/neu overexpression itself affects the expression of other RTK I members and that cells expressing the highest levels of HER-2/neu have the greatest response to HRG.

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Acknowledgements

The authors would like to thank Raul E Ayala for technical help and Judith Mitchell for secretarial assistance. We are grateful to Marie Jane Arboleda for her critical review of this manuscript. Z Aguilar received a scholarship from the `Consejo de Desarrollo Cientifico y Humanistico', Universidad Central de Venezuela. This work was funded by: NIH grant PO1 (CA32737), Department of Defense (DAMD17-94-J-4234) and the Revlon/UCLA Women's Cancer Research Program.

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  1. Division of Hematology and Oncology, Department of Medicine, UCLA School of Medicine, Los Angeles, 90095, California, CA, USA

    Zuleima Aguilar, Richard S Finn, B Lillian Ramos, Mark D Pegram, Fairooz F Kabbinavar, Richard J Pietras & Dennis J Slamon

  2. Genentech Inc., South San Francisco, 94080, California, CA, USA

    Robert W Akita, Paul Pisacane & Mark X Sliwkowski

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  1. Zuleima Aguilar
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Aguilar, Z., Akita, R., Finn, R. et al. Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cells. Oncogene 18, 6050–6062 (1999). https://doi.org/10.1038/sj.onc.1202993

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