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Open Access Highly Accessed Research article

Matrix metalloproteinase 1 and circulating tumor cells in early breast cancer

Zuzana Cierna1, Michal Mego235*, Pavol Janega16, Marian Karaba5, Gabriel Minarik4, Juraj Benca5, Tatiana Sedlácková4, Silvia Cingelova5, Paulina Gronesova7, Denisa Manasova2, Daniel Pindak58, Jozef Sufliarsky35, Ludovit Danihel1, James M Reuben9 and Jozef Mardiak35

Author Affiliations

1 Department of Pathology, Comenius University, Bratislava, Slovakia

2 Translational Research Unit, Comenius University, Bratislava, Slovakia

3 2nd Department of Medical Oncology, Comenius University, Faculty of Medicine, National Cancer Institute, Klenova 1, 833 10 Bratislava, Slovak Republic

4 Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia

5 National Cancer Institute, Bratislava, Slovakia

6 Institute of Normal and Pathological Physiology, Bratislava, Slovakia

7 Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia

8 Slovak Medical University, Bratislava, Slovakia

9 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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BMC Cancer 2014, 14:472  doi:10.1186/1471-2407-14-472

Published: 28 June 2014

Abstract

Background

Matrix metalloproteinases (MMPs) are involved in cancer invasion and metastasis. Circulating tumor cells (CTCs) play role in tumor dissemination and are an independent survival predictor in breast cancer (BC) patients. The aim of this study was to assess correlation between CTCs and tumor MMP1 in BC.

Methods

Study included 149 primary BC patients treated by surgery from March 2012 to March 2013. Peripheral blood mononuclear cells (PBMC) were depleted of hematopoietic cells using RossetteSepTM selection kit. RNA extracted from CD45-depleted PBMC was interrogated for expression of EMT (TWIST1, SNAIL1, SLUG, ZEB1) and epithelial (CK19) gene transcripts by qRT-PCR. Patient samples with higher epithelial and/or mesenchymal gene transcripts than those of healthy donors (n = 60) were considered as CTC positive. Expression of MMP1 in surgical specimens was evaluated by immunohistochemistry.

Results

CTCs were detected in 24.2% patients. CTCs exhibiting only epithelial markers were present in 8.7% patients, whereas CTCs with epithelial-mesenchymal transition (EMT) markers (CTC_EMT) were observed in 13.4% of patients and CTCs co-expressing both markers were detected in 2.0% patients. Patients with CTC_EMT in peripheral blood had significantly increased expression of MMP1 in tumor cells (p = 0.02) and tumor associated stroma (p = 0.05) than those of patients without CTC_EMT. In multivariate analysis, CTC_EMT and tumor grade were independently associated with MMP1 expression in cancer cells, while CTC_EMT and Ki67 were independently associated with MMP1 expression in cancer associated stroma.

Conclusion

Our data suggest link between MMP1 and CTCs with EMT phenotype and support role of MMPs and EMT in tumor dissemination.

Keywords:
Circulating tumor cells; Matrix-metaloproteinase 1; Primary breast cancer