FER drives tumor progression cues of invasive breast cancer cells through kinase-dependent control of proliferation and endosomal recycling

ABSTRACT: Triple-Negative Breast Cancer (TNBC) is a poorly targetable cancer subtype that exhibits a high metastatic potential. To develop new intervention strategies, it is crucial to understand the mechanisms governing migratory and invasive features of TNBC cells. Previously it was shown that high expression of the non-receptor tyrosine kinase FER is an independent prognostic factor that correlates with poor survival in high grade and basal breast cancer. Here, we show that FER controls proliferation and invasion of TNBC cells through the direct substrates MAPK1 and Dynactin 2 (DCTN2; Dynamitin). Our data demonstrate that FER regulates tumor cell proliferation through phosphorylation of MAPK1 on tyrosine 187, and recycling endosome function and subsequent invasion of breast cancer cells through tyrosine 6 residue (Y6) of DCTN2. We show that DCTN2-Y6 is essential for Dynein complex formation and the development of tubular recycling domains at the early endosome. By controlling this crucial step in endosomal recycling, FER drives and sustains adhesion and invasion of (triple negative) breast cancer cells. Our data provide clinical ramification by demonstrating that high grade and basal breast cancers expressing elevated FER levels are more susceptible to taxane-based chemotherapy interventions. In conclusion, our study links FER to kinase-dependent control of intracellular vesicular transport and tumor progression in breast cancer. Importantly, our results indicate that FER represents a predictive and functional biomarker in high grade basal breast cancers.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast Epithelial Cell, Epithelial Cell

DISEASE(S): Breast Cancer

SUBMITTER: Harmjan Vos  

LAB HEAD: Patrick W.B. Derksen

PROVIDER: PXD021307 | Pride | 2022-04-15

REPOSITORIES: Pride