JUNB governs a feed-forward network of TGFβ signaling that aggravates breast cancer invasion

Area of Science:

• Molecular Biology
• Cancer Research
• Cell Biology

Background:

• Transforming growth factor-β (TGFβ) paradoxically shifts from tumor suppressor to promoter during tumorigenesis.
• In breast cancer, SMAD mutations are rare, with SMAD interactions with other transcription factors driving oncogenesis.
• Understanding TGFβ's pro-oncogenic mechanisms in breast cancer is crucial for therapeutic development.

Purpose of the Study:

• To investigate how prolonged TGFβ stimulation alters the genome-wide binding landscape of SMAD2/3 in breast cancer cells.
• To identify key transcription factors and signaling pathways involved in TGFβ-induced breast cancer cell invasion.
• To elucidate the regulatory network stabilizing TGFβ-induced pro-oncogenic phenotypes.

Main Methods:

• Chromatin immunoprecipitation (ChIP)-sequencing to analyze SMAD2/3 binding.
• De novo motif analysis to identify enriched transcription factor binding sites.
• Gene expression analysis and pathway enrichment analysis (WNT, AP1).
• Functional assays involving overexpression and inhibition of WNT pathway components.

Main Results:

• Prolonged TGFβ stimulation significantly altered the genome-wide SMAD2/3 binding landscape.
• De novo motif analysis revealed enrichment of activator protein 1 (AP1) motifs alongside SMAD motifs.
• TGFβ-induced JUNB (an AP1 component) was essential for late invasion-mediating genes, forming a feed-forward loop.
• Components of the WNT pathway, including WNT7A/B, were enriched in late TGFβ-target genes and promoted TGFβ-induced invasion.

Conclusions:

• TGFβ signaling reprograms SMAD2/3 binding and induces a regulatory network involving AP1 and WNT pathways in breast cancer.
• This network stabilizes pro-oncogenic cellular phenotypes, driving cancer cell invasion.
• The findings provide insights into the mechanisms by which TGFβ promotes breast cancer progression.