American Association for Cancer Research
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Supplementary Figure Legends from WWOX Inhibits Metastasis of Triple-Negative Breast Cancer Cells via Modulation of miRNAs

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journal contribution
posted on 2023-03-31, 02:40 authored by Saleh Khawaled, Sung Suk Suh, Suhaib K. Abdeen, Jonathan Monin, Rosario Distefano, Giovanni Nigita, Carlo M. Croce, Rami I. Aqeilan

Supplementary Figure 1: Relapse-free survival (RFS) analysis for WWOX in KM plotter. Supplementary Figure 2: Relapse-free survival (RFS) analysis for the WWOX gene in TCGA dataset. Supplementary Figure 3: Boxplots for each comparison of the expression of the specific gene between WWOX+ (>75th percentile) and WWOX- (<25th percentile) samples. Supplementary Figure 4: WWOX restoration reduces proliferation and Matrigel invasion in vitro. Supplementary Figure 5: WWOX restoration attenuates mammary tumor growth and inhibits metastasis formation in vivo. Supplementary Figure 6: WWOX restoration inhibits metastasis formation and colonization in vivo. Supplementary figure 7: Effect of WWOX manipulation in TNBC cells. Supplementary figure 8: WWOX negatively regulates Fibronectin expression in vivo. Supplementary figure 9: WWOX overexpression modulates microRNAs expression. Supplementary figure 10: Inverse correlation between Fibronectin and miR-146a in TNBC samples. Supplementary Figure 11: miR-146a expression predicts improved survival in triple-negative breast cancer patients. Supplementary Figure 12: WWOX overexpression inhibits MYC activity. Supplementary figure 13: Densitometric quantification of all western blots.


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Harvey L. Miller Family Foundation




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. 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

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