WWOX Inhibits Metastasis of Triple-Negative Breast Cancer Cells via Modulation of miRNAs

Abstract

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 WWOXpositive 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.Significance: These findings highlight the mechanism by which the tumor suppressor WWOX regulates metastasis of triple-negative breast cancer.

Pleiotropic tumor suppressor functions of WWOX antagonize metastasis

“…[35][36][37] Our recent observations demonstrated that WWOX can regulate the levels of several miRNAs, which regulates TNBC metastasis. 34 In particular, we showed that WWOX could regulate the c-MYC/miR-146a/Fibronectin axis to antagonize TNBC invasion and tumor growth. 33,34 In other reports, it has been proposed that WWOX loss promotes metastasis of TNBC cells through regulating the JAK2/STAT3 axis, 38,39 further emphasizing the role of WWOX in antagonizing tumorigenesis.…”

“…34 In particular, we showed that WWOX could regulate the c-MYC/miR-146a/Fibronectin axis to antagonize TNBC invasion and tumor growth. 33,34 In other reports, it has been proposed that WWOX loss promotes metastasis of TNBC cells through regulating the JAK2/STAT3 axis, 38,39 further emphasizing the role of WWOX in antagonizing tumorigenesis. Moreover, a recent study showed that WWOX-deficient metastatic cells actively evade WWOX positive cells in their environment and then utilize various signaling pathways in order to force WWOX positive cells to undergo apoptosis, allowing further progression of metastasis.…”

“…Our previous work demonstrated that changes to WWOX are common in several cancers, and such changes are correlated with poor prognosis, including in BLBC and TNBC. 31,33,34 To further analyze the effect of WWOX on metastasis formation, we studied the differential expression of mRNAs using an Affymetrix GeneChip in WWOX-expressing and deficient metastatic cells. To this end, we performed mRNA profiling of MDA-MB435S metastatic melanoma cells expressing an empty-vector (EV), WWOX and a WWOX-WFPA mutant (Supplemental Fig.…”

“…[31][32][33] Indeed, both low copy number and reduced mRNA expression of WWOX are associated with advanced stages of TNBC, implying that WWOX plays a significant role in TNBC progression. 34 WWOX mediates many of its functions through its ability to interact with other proteins via its WW1 domain. [35][36][37] Our recent observations demonstrated that WWOX can regulate the levels of several miRNAs, which regulates TNBC metastasis.…”

The network of non-coding RNAs and their molecular targets in breast cancer

“…The FOXP3/miR-146/NF-kB axis limits tumour growth and could be a valuable target for therapy [200]. The role of miR-146a includes the reduction of fibronectin and opposing to the epithelial phenotype in TNBC subtype with a pro-metastatic activity supported via the oncosuppressor WWOX, that antagonizes MYC functions [201].…”