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ISRN Oncology
Volume 2013 (2013), Article ID 385398, 7 pages
http://dx.doi.org/10.1155/2013/385398
Research Article

Endothelin-1 Enriched Tumor Phenotype Predicts Breast Cancer Recurrence

1Department of Medicine, Michigan State University, B409 Clinical Center, East Lansing, MI 48824-1317, USA
2Department of Statistics and Probability, Michigan State University, 432A Wells Hall, East Lansing, MI 48824-1317, USA
3Department of Physiology, Michigan State University, 4164 Biomedical Physical Sciences, East Lansing, MI 48824, USA
4Department of Pathology, McLaren Regional Medical Center, 3490 Calkins Road, Flint, MI 48532, USA
5Michigan State University, B234 Life Science Building, East Lansing, MI 48824-1317, USA
6Pediatrics and Human Development, Michigan State University, B238 Life Science Building, East Lansing, MI 48824-1317, USA
7Michigan State University, 401 W Greenlawn Avenue, Lansing, MI 48910, USA
8Department of Medicine, Michigan State University, B413 Clinical Center, East Lansing, MI 48824-1317, USA

Received 9 April 2013; Accepted 9 May 2013

Academic Editors: Y. Akiyama, Z. S. Guo, S. Holdenrieder, T. Komiya, W. C. Mertens, and S. Patel

Copyright © 2013 Deimante Tamkus et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Introduction. Breast cancer recurrence can develop years after primary treatment. Crosstalk between breast cancer cells and their stromal microenvironment may influence tumor progression. Our primary study aim was to determine whether endothelin-1 (ET-1) expression in tumor and stroma predicts breast cancer relapse. The secondary aim was to determine ET-1/endothelin receptor A (ETAR) role on signaling pathways and apoptosis in breast cancer. Experimental Design. Patients with histologically documented stages I–III invasive breast cancer were included in the study. ET-1 expression by immunohistochemistry (IHC) in tumor cells and stroma was analyzed. Association between ET-1 expression and clinical outcome was assessed using multivariate Cox proportional hazard model. Kaplan-Meier curves were used to estimate disease-free survival (DFS). In addition, the effect of ET-1/ETAR on signaling pathways and apoptosis was evaluated in MCF-7 and MDA-MB-231 breast cancer cells. Results. With a median followup of 7 years, ET-1 non-enriched tumor phenotype had a significant association with favorable disease-free survival ( ; 95% CI 0.03–0.77; value <0.02). ER negativity, advanced stage of disease and ET-1-enriched tumor phenotype were all associated with a higher risk for recurrence. Experimental study demonstrated that ET-1 stimulation promoted Akt activation in MCF-7 and MDA-MB-231 cells. Furthermore, silencing of ETAR induced apoptosis in both hormone receptor negative and hormone receptor positive breast cancer cells. Conclusions. We found ET-1 expression in tumor and stroma to be an independent prognostic marker for breast cancer recurrence. Prospective studies are warranted to examine whether ET-1 expression in tumor/stroma could assist in stratifying patients with hormone receptor positive breast cancer for adjuvant therapy.