This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, Q. Articles by Loeb, J. A. Search for Related Content PubMed PubMed Citation Articles by Li, Q. Articles by Loeb, J. A.

Development of an Autocrine Neuregulin Signaling Loop with Malignant Transformation of Human Breast Epithelial Cells

¹ Department of Neurology and ² Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan

Neuregulin (NRG) is a heparin-binding factor that activates members of the epidermal growth factor family of tyrosine kinase receptors including erbB2 that is overexpressed in more aggressive types of breast cancer. The exact role that NRG plays in breast cancer is complicated by the fact that NRG has been shown to have both proliferative and antiproliferative effects, depending on the breast cancer cell line used. Using an isogenic series of breast epithelial cell lines (MCF10A) ranging from benign to malignant, we found that the actions of NRG changed from antiproliferative to proliferative as the cells progress to cancer. This correlated with a progressive inability of NRG to down-regulate a group of proliferation genes identified previously using cDNA microarrays. As the cells progress to malignancy, they expressed higher levels of erbB2 and lower levels of erbB3 and secreted high levels of NRG into the culture media, resulting in high basal levels of erbB receptor phosphorylation. Disruption of this autocrine signaling loop by blocking ligand-induced receptor activation inhibited cancer cell proliferation. These results demonstrate that the transition of MCF10A cells from normal to premalignant to malignant correlates with the development of a constitutively active autocrine NRG signaling loop that promotes cell proliferation and suggest that disrupting this autocrine loop may provide an important therapeutic measure to control breast cancer cell growth.

This article has been cited by other articles:

				Z. Ma, Q. li, H. An, M. S. Pankonin, J. Wang, and J. A. Loeb Targeting Human Epidermal Growth Factor Receptor Signaling with the Neuregulin's Heparin-binding Domain J. Biol. Chem., November 13, 2009; 284(46): 32108 - 32115. [Abstract] [Full Text] [PDF]

				O. Meurette, S. Stylianou, R. Rock, G. M. Collu, A. P. Gilmore, and K. Brennan Notch Activation Induces Akt Signaling via an Autocrine Loop to Prevent Apoptosis in Breast Epithelial Cells Cancer Res., June 15, 2009; 69(12): 5015 - 5022. [Abstract] [Full Text] [PDF]

				E. Yao, W. Zhou, S. T. Lee-Hoeflich, T. Truong, P. M. Haverty, J. Eastham-Anderson, N. Lewin-Koh, B. Gunter, M. Belvin, L. J. Murray, et al. Suppression of HER2/HER3-Mediated Growth of Breast Cancer Cells with Combinations of GDC-0941 PI3K Inhibitor, Trastuzumab, and Pertuzumab Clin. Cancer Res., June 15, 2009; 15(12): 4147 - 4156. [Abstract] [Full Text] [PDF]

				K. Nagata, K. Wada, A. Tatsuguchi, S. Futagami, K. Gudis, K. Miyake, T. Tsukui, and C. Sakamoto Heregulin-{alpha} and heregulin-beta expression is linked to a COX-2-PGE2 pathway in human gastric fibroblasts Am J Physiol Gastrointest Liver Physiol, June 1, 2006; 290(6): G1243 - G1251. [Abstract] [Full Text] [PDF]

				D. N. Amin, K. Hida, D. R. Bielenberg, and M. Klagsbrun Tumor Endothelial Cells Express Epidermal Growth Factor Receptor (EGFR) but not ErbB3 and Are Responsive to EGF and to EGFR Kinase Inhibitors Cancer Res., February 15, 2006; 66(4): 2173 - 2180. [Abstract] [Full Text] [PDF]