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 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. SIGNIFICANCE: These findings highlight the mechanism by which the tumor suppressor WWOX regulates metastasis of triple-negative breast cancer.See related commentary by Sharma, p. 1746.
Highlights
Triple-negative breast cancers [ER(À)/PR(À)/HER2wt (TNBC)] are highly aggressive breast cancers with well-known association with epithelial-to-mesenchymal transition (EMT), undifferentiated metaplastic histology, stem cell–like characteristics, invasiveness, higher metastatic potential, and inconsistently effective therapies [1]
We found that the majority of advanced stages of TNBC cases harbor low copy number variation (CNV) of WWOX (Fig. 1A and B; cor 1⁄4 À0.86; P value (pV) 1⁄4 0.0028)
We investigated the effect of WWOX changes in TNBC and identified that its reduced expression and low CNVs are correlated with advanced TNBC stages and predicts worse TNBC outcome
Summary
Triple-negative breast cancers [ER(À)/PR(À)/HER2wt (TNBC)] are highly aggressive breast cancers with well-known association with epithelial-to-mesenchymal transition (EMT), undifferentiated metaplastic histology, stem cell–like characteristics, invasiveness, higher metastatic potential, and inconsistently effective therapies [1]. TNBCs are viewed clinically as an aggressive subtype, with an earlier age of presentation and requiring adjuvant chemotherapy to improve survival. TNBCs display high mutation rate in TP53 and PI3K3CA, but other infrequent somatic mutations affecting PTEN, RB1, NF1, BRCA1, BRCA2, ERBB3, ERBB4, ALK, have been reported in small subsets of TNBCs [1, 2]. There is an urgent demand in identifying additional molecular events and signaling path-
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