RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation.

Mònica Morales,Joan Massagué,Roger R Gomis,Xavier Salvatella,Enrique J Arenas,Marc Guiu,Sonia Fernández‐Ruiz,Evarist Planet,Arkaitz Carracedo,David Reverter,Robert Bryn Fenwick,Jelena Urosevic,Esther Fernández

doi:10.15252/emmm.201303675

Abstract

In estrogen receptor-negative breast cancer patients, metastatic relapse usually occurs in the lung and is responsible for the fatal outcome of the disease. Thus, a better understanding of the biology of metastasis is needed. In particular, biomarkers to identify patients that are at risk of lung metastasis could open the avenue for new therapeutic opportunities. Here we characterize the biological activity of RARRES3, a new metastasis suppressor gene whose reduced expression in the primary breast tumors identifies a subgroup of patients more likely to develop lung metastasis. We show that RARRES3 downregulation engages metastasis-initiating capabilities by facilitating adhesion of the tumor cells to the lung parenchyma. In addition, impaired tumor cell differentiation due to the loss of RARRES3 phospholipase A1/A2 activity also contributes to lung metastasis. Our results establish RARRES3 downregulation as a potential biomarker to identify patients at high risk of lung metastasis who might benefit from a differentiation treatment in the adjuvant programme.

Highlights

Breast cancer (BC) is a highly heterogeneous disease, and there is clinical evidence of distinct patterns of disease relapse (Kennecke et al, 2010)
We confirmed the inverse association of RARRES3 expression with lung metastasis previously described in the MSKCC primary breast cancer set (n = 82) and, in those tumors defined as positive according to the lung metastasis signature (LMS) (Minn et al, 2005) (Fig 1A)
The reduced expression of RARRES3 in primary tumors was significantly associated with the risk of lung metastasis (Fig 1B)

Summary

Introduction

Breast cancer (BC) is a highly heterogeneous disease, and there is clinical evidence of distinct patterns of disease relapse (Kennecke et al, 2010). Among the set of genes whose expression in breast tumor is associated with lung relapse, several encoded cytokines or secreted products that supported transendothelial migration from circulation into the lung parenchyma (Gupta et al, 2007; Padua et al, 2008). Additional genes, such as the extracellular matrix protein TNC, support the critical stem and progenitor cell pathways NOTCH and WNT and the viability of metastatic cancer cells in the lungs (Oskarsson et al, 2011). RARRES3, a member of the lung metastasis gene signature (LMS) previously described (Minn et al, 2005), was identified in this group of genes as a potential metastasis suppressor

Methods

Results

Conclusion