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Modulation of breast cancer progression and differentiation by thegp30/neregulin

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Summary

In the last decade we have come to understand that the growth of cancer cells in general and of breast cancer in particular depends, in many cases, upon growth factors that will bind to and activate their receptors. One of these growth factor receptors is theerbB-2 protein which plays an important role in the prognosis of breast cancer and is overexpressed in nearly 30% of human breast cancer patients. While evidence accumulates to support the relationship betweenerbB-2 overexpression and poor overall survival in breast cancer, understanding of the biological consequence(s) oferbB-2 overexpression remains elusive. Our recent discovery of thegp30 has allowed us to identify a number of related but distinct biological endpoints which appear responsive to signal transduction through theerbB-2 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 breast cancer. We have shown thatgp30 induces a biphasic growth effect on cells witherbB-2 over-expression. We have recently determined the protein sequence ofgp30 and cloned its full length cDNA sequence. We have also cloned two additional forms to the ligand, that are believed to be different isoforms. We are currently expressing the different forms in order to determine their biological effects. To elucidate the cellular mechanisms underlying cell growth inhibition bygp30, we tested the effect of this ligand on cell growth and differentiation of the human breast cancer cells which overexpresserbB-2 and cells which express low levels of this protooncogene. High concentrations of ligand induced differentiation of cells overexpressingerbB-2, as measured by inhibition of cell growth, and increased synthesis of milk components, and modulation of E-cadherin and up-regulation of c-jun and c-fos. These findings indicate that ligand-induced growth inhibition in cells overexpressingerbB-2 is associated with an apparent induction of differentiation. The availability ofgp30 derived synthetic peptides and its full cDNAs provides tools necessary to acquire a better understanding of the mechanism of action of the this ligands and theerbB-2 receptor in breast cancer.

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Authors and Affiliations

  1. V.T. Lombardi Cancer Research Center, Georgetown University Medical Center, 3800 Reservoir Road NW, 20007, Washington, DC, USA

    A. Staebler, C. Sommers, S. C. Mueller, S. Byers, E. W. Thompson & R. Lupu

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  1. A. Staebler
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  2. C. Sommers
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  3. S. C. Mueller
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  4. S. Byers
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  5. E. W. Thompson
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  6. R. Lupu
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Staebler, A., Sommers, C., Mueller, S.C. et al. Modulation of breast cancer progression and differentiation by thegp30/neregulin. Breast Cancer Res Tr 31, 175–182 (1994). https://doi.org/10.1007/BF00666151

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