RARRES 3 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 RARRES 3 , 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 RARRES 3 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 RARRES 3 phospholipase A 1/ A 2 activity also contributes to lung metastasis. Our results establish RARRES 3 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. image Loss of RARRES 3 facilitates breast cancer cell extravasation, lung extracellular matrix adherence, and lung colonization. Furthermore, RARRES 3 levels in the primary tumor may predict risk of relapse and might help identify therapy‐resistant tumors. Low expression levels of RARRES 3 in ER ‐negative primary breast tumors identify patients at high risk of developing lung metastasis. RARRES 3 suppresses lung metastasis in ER ‐negative breast cancer cells. RARRES 3 depletion facilitates the adhesion of breast cancer cells to lung parenchyma and metastasis initiation. Loss of RARRES 3 phospholipase A 1/ A 2 activity impairs tumor cell differentiation and is crucial for metastasis initiation.