Human NUMB6 Induces Epithelial-Mesenchymal Transition and Enhances Breast Cancer Cells Migration and Invasion

Area of Science:

• Molecular Biology
• Cell Biology
• Oncology

Background:

• Mammalian NUMB protein has tumor-suppressive isoforms (NUMB1-NUMB4).
• Novel NUMB isoforms (NUMB5, NUMB6) exhibit pro-oncogenic functions.
• NUMB1-NUMB4 are reduced in 21% of primary breast tumors.

Purpose of the Study:

• To investigate the novel function of human NUMB isoform 6 (NUMB6) in promoting cancer cell migration and invasion.
• To elucidate the molecular mechanisms underlying NUMB6's role in breast cancer progression.

Main Methods:

• Stable expression of NUMB6 in low-metastatic breast cancer cells (DB-7).
• Analysis of epithelial-mesenchymal transition (EMT) markers, including Slug, E-cadherin, vimentin, β-catenin, and fibronectin.
• Assessment of metalloproteinase 9 (MMP9) production.
• Evaluation of Akt1 and Akt2 phosphorylation levels.
• Inhibition of Akt signaling using LY294002.

Main Results:

• NUMB6 expression induced Slug, repressing E-cadherin and promoting EMT.
• NUMB6-expressing cells exhibited migratory and invasive behavior with increased mesenchymal markers.
• Elevated vimentin, β-catenin, and fibronectin expression correlated with increased MMP9 production.
• NUMB6-expressing cells showed increased Akt1/Akt2 phosphorylation.
• Inhibition of Akt signaling reduced Slug expression, cell migration, and invasion.

Conclusions:

• NUMB6 is a novel molecular determinant of breast cancer progression.
• NUMB6 plays a potential oncogenic role in promoting cancer cell migration and invasion.
• NUMB6 contributes to the maintenance of mesenchymal-like cancer cells.