%0 Journal Article
%T Endothelin-1 Enriched Tumor Phenotype Predicts Breast Cancer Recurrence
%A Deimante Tamkus
%A Alla Sikorskii
%A Kathleen A. Gallo
%A David A. Wiese
%A Cheryl Leece
%A Burra V. Madhukar
%A Simona C. Chivu
%A Shalini Chitneni
%A Nikolay V. Dimitrov
%J ISRN Oncology
%D 2013
%R 10.1155/2013/385398
%X 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¨CIII 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¨C0.77; 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. 1. Introduction Breast cancer metastases can develop years after primary tumor treatment [1]. Current adjuvant systemic or regional therapies eliminate a majority of cancer cells. However, a subset of cancer cells, which are not effectively eradicated by the treatment, may maintain their potential for further growth. Tumor cells may interact with their stromal microenvironment to either facilitate or delay tumor dissemination, thus influencing tumor recurrence in breast cancer patients [2]. Thirty to 40% of patients with early-stage breast cancer at the time of diagnosis have disseminated tumor cells detected in the bone marrow [3]. The majority of these disseminated tumor cells die, but some of them remain dormant and have the capacity to
%U http://www.hindawi.com/journals/isrn.oncology/2013/385398/