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A deletion mutant of heregulin increases the sensitivity of breast cancer cells to chemotherapy without promoting tumorigenicity

Oncogene volume 22, pages 3441–3451 (2003)Cite this article

Abstract

Heregulin (HRG) is an activator of the erbB2-, erbB3- and erbB4-(erbB-2/3/4) signaling pathway. Transfection of full-length HRG cDNA into the estrogen (E2)-dependent cell line MCF-7 promoted an invasive E2-independent phenotype, as well as persistent activation of the erbB-2/3/4 receptors. Moreover, HRG expression in MCF-7 cells renders the cells sensitive to the topoisomerase II inhibitor doxorubicin (Doxo). In an attempt to dissociate the tumorigenic effect of HRG from the sensitizing effect to chemotherapy, we constructed a structural deletion mutant of HRG. Transfection of the deletion mutant of HRG described in this study (HRG/M) into MCF-7 cells resulted in the dissociation of the tumor-promoting activity of HRG from the sensitization to Doxo, that is, although the cells did not become more aggressive or E2-independent they became more sensitive to Doxo. HRG/M was unable to autophosphorylate the erbB receptors and did not affect the level of MAPK phosphorylation. Furthermore, the intracellular localization of the protein was different from that of the full-length protein. Our data show that the HRG/M sequences are sufficient to sensitize MCF-7 cells to Doxo, and provide evidence that this sensitization is independent of erbB2 activation.

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Acknowledgements

This work was supported by a grant from the Komen Foundation for Breast Cancer Research and the Department of Energy under Contract No. DE-AC03-76SF00098 (RL), and the National Cancer Institute of Canada (EA).

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  1. Kozystof Bojanowski

    Present address: Sunny BioDiscovery, 675 Hegenberger Rd., Oakland, CA, 94621, USA

Authors and Affiliations

  1. Evanston Northwestern Healthcare Research Institute, Northwestern University, 1001 University Place, 2650 Ridge Avenue Evanston, 60201, IL, USA

    Ella Atlas, Kozystof Bojanowski, Inderjit Mehmi & Ruth Lupu

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  1. Ella Atlas
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Correspondence to Ruth Lupu.

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Atlas, E., Bojanowski, K., Mehmi, I. et al. A deletion mutant of heregulin increases the sensitivity of breast cancer cells to chemotherapy without promoting tumorigenicity. Oncogene 22, 3441–3451 (2003). https://doi.org/10.1038/sj.onc.1206410

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