Importance of nuclear translocation of AXL in breast cancer
Date
2022
DOI
Authors
Graham, Darby
Version
OA Version
Citation
Abstract
AXL is a receptor tyrosine kinase (RTK) that is activated by ligand-dependent and independent manners and is involved in proliferation, cell survival, and clearance of apoptotic cells in both normal physiology and a number of disease states. Clinically, AXL is overexpressed in Her2+ and triple-negative breast cancers. Previous studies have shown that upon kinase inhibition, the AXL intracellular domain (ICD) can translocate to the nucleus, however, the biological significance and functions for nuclear AXL are poorly understood. Furthermore, a functional role for AXL during the progression from ductal carcinoma in situ (DCIS), a non-obligate precursor to breast cancer, to invasive ductal carcinoma (IDC), has not been established. To address whether AXL mediates DCIS progression to invasive cancer, AXL was deleted in a DCIS cell line (MCF10A-DCIS.com) using a CRISPR-Cas9 approach. Deletion of AXL shows a significant decrease in progression to invasive cancer in vivo using the mammary intraductal (MIND) model. Analysis of patient samples before chemotherapy of pure DCIS, DCIS with microinvasion, and DCIS with invasive cancer shows a significant increase in AXL expression in patients with evidence of invasion. Additionally, there is a significant increase in nuclear AXL in patient samples with increased invasive components as compared to earlier stages and normal breast samples. These results are suggestive of an important role for AXL-ICD in progression to invasive cancer.
Ongoing studies are aimed at identifying transcriptional targets of AXL-ICD in DCIS cells. During this research thesis, it was found by western blot analysis that AXL-ICD enhanced C/EBPβ expression, elucidating a potential nuclear target. RNA isolated from the AXL knockdown and AXL overexpression cell lines were sent for RNA sequencing which will give us a greater understanding of the role AXL-ICD plays in tumor progression, including potential confirmation of C/EBPβ as a downstream target of AXL-ICD. Ultimately, these studies will advance our understanding of how AXL mediates breast cancer progression and will have crucial implications for developing new therapeutics to target AXL-positive breast cancers.
Description
License
Attribution 4.0 International