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HER-2 overexpression differentially alters transforming growth factor-β responses in luminal versus mesenchymal human breast cancer cells

Wilson, Cindy A. and Cajulis, Elaina E. and Green, Jennifer L. and Olsen, Taylor M. and Chung, Young Ah and Damore, Michael A. and Dering, Judy and Calzone, Frank J. and Salmon, Dennis J. (2005) HER-2 overexpression differentially alters transforming growth factor-β responses in luminal versus mesenchymal human breast cancer cells. Breast Cancer Research, 7 (6). R1058-R1079. ISSN 1465-5411. http://resolver.caltech.edu/CaltechAUTHORS:WILbcr05

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Abstract

Introduction: Amplification of the HER-2 receptor tyrosine kinase has been implicated in the pathogenesis and aggressive behavior of approximately 25% of invasive human breast cancers. Clinical and experimental evidence suggest that aberrant HER-2 signaling contributes to tumor initiation and disease progression. Transforming growth factor beta (TGF-β) is the dominant factor opposing growth stimulatory factors and early oncogene activation in many tissues, including the mammary gland. Thus, to better understand the mechanisms by which HER-2 overexpression promotes the early stages of breast cancer, we directly assayed the cellular and molecular effects of TGF-β1 on breast cancer cells in the presence or absence of overexpressed HER-2. Methods: Cell proliferation assays were used to determine the effect of TGF-β on the growth of breast cancer cells with normal or high level expression of HER-2. Affymetrix microarrays combined with Northern and western blot analysis were used to monitor the transcriptional responses to exogenous TGF-β1 in luminal and mesenchymal-like breast cancer cells. The activity of the core TGF-β signaling pathway was assessed using TGF-β1 binding assays, phospho-specific Smad antibodies, immunofluorescent staining of Smad and Smad DNA binding assays. Results: We demonstrate that cells engineered to over-express HER-2 are resistant to the anti-proliferative effect of TGF-β1. HER-2 overexpression profoundly diminishes the transcriptional responses induced by TGF-β in the luminal MCF-7 breast cancer cell line and prevents target gene induction by a novel mechanism that does not involve the abrogation of Smad nuclear accumulation, DNA binding or changes in c-myc repression. Conversely, HER-2 overexpression in the context of the mesenchymal MDA-MB-231 breast cell line potentiated the TGF-β induced pro-invasive and pro-metastatic gene signature. Conclusion: HER-2 overexpression promotes the growth and malignancy of mammary epithelial cells, in part, by conferring resistance to the growth inhibitory effects of TGF-β. In contrast, HER-2 and TGF-β signaling pathways can cooperate to promote especially aggressive disease behavior in the context of a highly invasive breast tumor model.


Item Type:Article
Additional Information: © 2005 Wilson et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The electronic version of this article is the complete one and can be found online at: http://breast-cancer-research.com/content/7/6/R1058 Competing interests: DJS, CAW and FIC have a related patent pending. Authors' contributions: CAW, FJC and DJS conceived of the study and participated in its design. CAW and FJC coordinated the experiments and drafted the manuscript. EEC isolated RNAs and performed Northern blotting analysis, JLG carried out the assays to determine the activity and location of the Smad proteins, and TMO and YAC carried out the cell proliferation assays. MAD carried out the Affymetrix microarray experiments and JD helped with the analysis of the microarray expression data. All authors read and approved the final manuscript. Acknowledgements: This study was supported by funds from the Revlon/UCLA Women's Cancer Research Program, NIH grant PO1CA32737, an Amgen sponsored UC BioStar grant and by CBCRP grant 8WB-0159.
Record Number:CaltechAUTHORS:WILbcr05
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:WILbcr05
Alternative URL:http://dx.doi.org/10.1186/bcr1343
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1127
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:21 Dec 2005
Last Modified:07 Nov 2013 20:08

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