RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation

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.We would like to thank the Functional Genomics, Microscopy, and Cytometry core facilities of IRB Barcelona, and the UB. We thank C. Caelles for the 3AOX-luc construct. We thank Angel Nebreda for his scientific suggestions. EJA is supported by "La Caixa" PhD fellowship programme, and JU is a Juan de la Cierva Researcher (MICINN). JM is a Howard Hughes investigator. The work of A. C. and S.F-R is supported by the Ramon y Cajal award to AC (Spanish Ministry of Education) and the ERC (336343). JM was supported by HHMI. RRG and XS are ICREA Research Professors (Institucio Catalana de Recerca i Estudis Avancats). Support and structural funds were provided by the Associacion Espanola Contra el Cancer (AECC), Fundacion BBVA, Generalitat de Catalunya (2009 SGR 1429), and Spanish Ministerio de Ciencia e Innovacion (MICINN) (SAF2010-21171) to RRG