TGFβ Governs the Pleiotropic Activity of NDRG1 in Triple-Negative Breast Cancer Progression

Abstract

In triple-negative breast cancer (TNBC), the pleiotropic NDRG1 (N-Myc downstream regulated gene 1) promotes progression and worse survival, yet contradictory results were documented, and the mechanisms remain unknown. Phosphorylation and localization could drive NDRG1 pleiotropy, nonetheless, their role in TNBC progression and clinical outcome was not investigated. We found enhanced p-NDRG1 (Thr346) by TGFβ1 and explored whether it drives NDRG1 pleiotropy and TNBC progression. In tissue microarrays of 81 TNBC patients, we identified that staining and localization of NDRG1 and p-NDRG1 (Thr346) are biomarkers and risk factors associated with shorter overall survival. We found that TGFβ1 leads NDRG1, downstream of GSK3β, and upstream of NF-κB, to differentially regulate migration, invasion, epithelial-mesenchymal transition, tumor initiation, and maintenance of different populations of cancer stem cells (CSCs), depending on the progression stage of tumor cells, and the combination of TGFβ and GSK3β inhibitors impaired CSCs. The present study revealed the striking importance to assess both total NDRG1 and p-NDRG1 (Thr346) positiveness and subcellular localization to evaluate patient prognosis and their stratification. NDRG1 pleiotropy is driven by TGFβ to differentially promote metastasis and/or maintenance of CSCs at different stages of tumor progression, which could be abrogated by the inhibition of TGFβ and GSK3β.

Association between NDRG1 protein expression and aggressive features of breast cancer: a systematic review and meta-analysis

“…Among them, 100 were further examined for full text according to the eligible criteria. Finally, six studies [ 21 – 26 ] met the eligible criteria were included for syntheses (Fig. 1 ).…”

“…Studies were published between 2011 and 2023 (Table 1 ). Four studies were cohort [ 21 , 22 , 24 , 26 ], and two were cross-sectional studies [ 23 , 25 ]. Four studies enrolled patients with invasive breast cancers [ 22 , 23 , 25 , 26 ].…”

“…Four studies enrolled patients with invasive breast cancers [ 22 , 23 , 25 , 26 ]. Meanwhile, other studies enrolled patients with inflammatory breast cancer [ 24 ] and only triple-negative breast cancer [ 21 ]. Four studies used immunohistochemistry for detection of NDRG1 protein expression [ 21 , 22 , 24 , 26 ].…”

“…Meanwhile, other studies enrolled patients with inflammatory breast cancer [ 24 ] and only triple-negative breast cancer [ 21 ]. Four studies used immunohistochemistry for detection of NDRG1 protein expression [ 21 , 22 , 24 , 26 ]. Meanwhile, another study used only tissue microarrays [ 25 ], and another study used both tissue microarrays and immunohistochemistry methods for the detection of NDRG1 protein expression [ 23 ].…”

Small molecule agents for triple negative breast cancer: Current status and future prospects

“…Its expression level in TNBC tissues is significantly higher than that in non-TNBC tissues, which is closely associated with OS and PFS of TNBC patients [277] . TGF-β can drive the pleiotropy of NDRG1 to differentially regulate CSC and EMT of TNBC at different stages to promote metastasis [278] . Inhibiting the activation of the TGF-β1 pathway can prevent the EMT, thus preventing the progression of TNBC [279] .…”