CD44 activation state regulated by the CD44v10 isoform determines breast cancer proliferation

The cell surface glycoprotein CD44 displays different active statuses; however, it remains unknown whether the activation process of CD44 is critical for tumor development and progression. The aim of the present study was to investigate whether breast cancer (BCa) cells with different activation states of CD44 show similar or distinct functional characteristics and to further examine the mechanisms regulating CD44 activities. A feature for the 'activated' state of CD44 is that it can bind to its principal ligand hyaluronan (HA). The binding of CD44 with HA is usually influenced by CD44 alternative splicing, resulting in multiple CD44 isoforms that determine CD44 activities. Flow cytometry was used to sort BCa cell subsets based on CD44-HA binding abilities (HA(-/low) vs. HA(high)). Subsequently, cell proliferation and colony formation assays were performed in vitro, and CD44 expression patterns were analyzed via western blotting. The results demonstrated that the CD44 variant isoform 10 (CD44v10) was highly expressed in a HA(-/low) binding subset of BCa cells, which exhibited a significantly higher proliferation capacity compared with the HA(high) binding subpopulation. Knockdown of CD44v10 isoform in HA(-/low) binding subpopulation induced an increase in HA binding ability and markedly inhibited proliferation. Furthermore, the mechanistic analysis identified that CD44v10 facilitated cell proliferation via activation of ERK/p38 MAPK and AKT/mTOR signaling. Moreover, the knockdown of CD44v10 expression downregulated the phosphorylation of ERK, AKT and mTOR, while no alteration was observed in p38 phosphorylation. Collectively, the present study identified a subset of fast-growing BCa cells characterized by CD44v10 expression, which may serve as a specific therapeutic target for BCa.