Triple-negative breast cancer (TNBC) is a heterogeneous, highly aggressive, and difficult to treat tumor type. The tumor suppressor WWOX spans FRA16D, a common fragile site that is commonly altered in breast cancer. Despite recent progress, the role of WWOX in TNBC metastasis is unknown. Here we report that WWOX inactivation correlates with advanced stages of TNBC and that its levels are frequently altered in TNBC cells. Ectopic restoration of WWOX in WWOX-negative TNBC cells inhibited metastasis while its depletion in WWOX-positive TNBC cells promoted metastasis. WWOX was a negative regulator of c-MYC, which regulated miR-146a expression and consequently fibronectin levels, contributing to an epithelial status of the cell. Treatment of TNBC cells with anti-miR-146a rescued the WWOX antimetastatic phenotype. Moreover, overexpression of MYC in WWOX-expressing TNBC cells overrode WWOX effects on miR-146a and fibronectin levels. Altogether, our data uncover an essential role for WWOX in antagonizing TNBC progression and highlight its potential use as a biomarker for metastasis.
Bibliographical noteFunding Information:
We are grateful for all the Aqeilan's lab members for fruitful discussions. Special thanks to Mr. Mayur Tanna for technical help and for Ms. Sara Oster for critical reading of the manuscript. The Aqeilan lab is supported by the Israel Science Foundation Grant (grant agreement no. 15/1574), ICRF-City of Hope - Harvey L. Miller Family Foundation, and European Research Council (ERC)-Consolidator Grant under the European Union's Horizon 2020 Research and Innovation programme (grant agreement no. 682118).
© 2019 American Association for Cancer Research.