Background: Epithelial mesenchymal plasticity (EMP) is deemed vital in breast cancer progression, metastasis, stemness and resistance to therapy. Therefore, characterizing molecular mechanisms contributing to EMP are in need enabling the development of more advanced therapeutics against breast cancer. While kinesin superfamily proteins (KIFs) are well known for their role in intracellular cargo movement, our knowledge of their function in breast tumorigenesis is still limited.
Methods: Various breast cancer cell lines representing different molecular subtypes were used to determine the role of kinesine-1 subunits KIF5B/KLC1 in regulation of EMP.
Findings: In breast cancer, we show that kinesin family member 5B (KIF5B) and its partner protein kinesin light chain 1 (KLC1), subunits of kinesin-1, to play differential roles in regulating EMP and tumorigenesis. Indeed, we found KIF5B to be expressed in triple negative (TN)-basal-like/claudin low breast cancer subtype and to be an inducer of epithelial-mesenchymal transition (EMT), stemness, invasiveness, tumor formation and metastatic colonization. Whereas, we found KLC1 to be expressed in epithelial/luminal breast cancer subtypes and to be a suppressor of EMT, invasion, metastasis and stem cell markers expression as well as to be an inducer of epithelial/luminal phenotype. Interestingly, in TN-basal-like/claudin low cells we found a novel nuclear accumulation of KIF5B and its interaction with the EMT transcriptional regulator Snail1 independent of KLC1. In addition, TGF-β mediated pro-invasive activity was found to be dependent on KIF5B expression. In contrast, the epithelial differentiation factor and EMT suppressor prolactin (PRL) was found to repress KIF5B gene expression and KIF5B-Snail1 nuclear accumulation, but enhanced KLC1 gene expression and KIF5B-KLC1 interaction.
Interpretation: Together, these results highlight a new paradigm for kinesin-1 function in breast tumorigenesis by regulating EMP programing and aggressiveness. FUND: This work was supported by the Canadian Institutes of Health Research (operating grants #233437 and 233438) granted to Suhad Ali.
Keywords: Cancer stem cells; Differentiation; EMT; Epithelial mesenchymal plasticity; Invasion; KIF5B; KLC1; Prolactin; TGFβ; Xenograft.
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.