RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation

EMBO Molecular Medicine

Mònica Morales²  Enrique J Arenas²  Jelena Urosevic²  Marc Guiu²  Esther Fernández²  Evarist Planet⁴  Robert Bryn Fenwick¹  Sonia Fernández-Ruiz⁵  Xavier Salvatella¹  David Reverter³  Arkaitz Carracedo⁵  Joan Massagué⁶ 

[1] Joint BSC-IRB Research Programme in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain;Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain;Departament de Bioquímica i de Biologia Molecular, Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain;Biostatistics and Bioinformatics Unit, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain;CIC bioGUNE, Bizkaia Tecnology park, Derio, Spain;Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

关键词: breast cancer;    lung metastasis;    metastasis suppressor;   

DOI  :  10.15252/emmm.201303675

来源: Wiley

【 摘 要 】

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.

Synopsis

Loss of RARRES3 facilitates breast cancer cell extravasation, lung extracellular matrix adherence, and lung colonization. Furthermore, RARRES3 levels in the primary tumor may predict risk of relapse and might help identify therapy-resistant tumors.

• Low expression levels of RARRES3 in ER-negative primary breast tumors identify patients at high risk of developing lung metastasis.
• RARRES3 suppresses lung metastasis in ER-negative breast cancer cells.
• RARRES3 depletion facilitates the adhesion of breast cancer cells to lung parenchyma and metastasis initiation.
• Loss of RARRES3 phospholipase A1/A2 activity impairs tumor cell differentiation and is crucial for metastasis initiation.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.