FER regulates endosomal recycling and is a predictor for adjuvant taxane benefit in breast cancer

Elevated expression of non-receptor tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/triple-negative breast cancer (TNBC) patients. Here, we show that high FER levels are also associated with improved outcomes after adjuvant taxane-based combination chemotherapy in high-risk, HER2-negative patients. In TNBC cells, we observe a causal relation between high FER levels and sensitivity to taxanes. Proteomics and mechanistic studies demonstrate that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identify DCTN2 as a FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for the development of tubular recycling domains in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for the benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients.

Automated summary

Elevated expression of non-receptor tyrosine kinase FER is associated with poor prognosis in breast cancer patients, particularly in high-grade and basal/triple-negative cases. However, high FER levels are correlated with improved outcomes after adjuvant taxane-based chemotherapy in high-risk, HER2-negative patients. Mechanistic studies reveal that FER regulates endosomal recycling and its inhibition leads to reduced breast cancer cell invasion. Furthermore, DCTN2 is identified as a substrate of FER, and its phosphorylation at tyrosine 6 is essential for tubular recycling domains formation and TNBC cell invasion.