The transcriptional regulator Sin3a activates CD44 and promotes collective luminal breast cancer cell migration.

Luminal type breast cancer (BrCa) cells invade into the surrounding tissues as collective strands, making them more metastatic than single cells. We have previously reported that the leading subpopulation of collective cells expressed high levels of CD44, which was associated with enhanced migratory and invasive potential of BrCa. It is crucial to elucidate how CD44 becomes enriched in leader cells and contributes to collective migration. In this study, we aimed to uncover the mechanisms responsible for CD44 upregulation in this context. First, we demonstrated that CD44 could facilitate dynamic lamellipodia formation by interacting with cytoskeletal proteins through its cytoplasmic domain. Then, we identified that a transcriptional regulator, Sin3a, was remarkably upregulated at the front edge of collectively migrating cells, exhibiting a correlation with enhanced CD44 expression. Notably, the knockdown of Sin3a effectively suppressed CD44 enrichment and lamellipodia outgrowth in leader cells, resulting in a significantly decreased cohesive movement of BrCa cells in vitro and in vivo. Our findings suggested that Sin3a was a novel regulator in CD44-facilitated lamellipodia formation and subsequent collective migration. This study elucidated the molecular mechanism underlying CD44 upregulation during collective migration of luminal-type BrCa cells, providing potential therapeutic targets to prevent cancer metastasis.