Nuclear Localized LSR: A Novel Regulator of Breast Cancer Behavior and Tumorigenesis

Abstract

Lipolysis Stimulated Lipoprotein Receptor (LSR) has been found in the plasma membrane and is believed to function in lipoprotein endocytosis and tight junctions. Given the impact of cellular metabolism and junction signaling pathways on tumor phenotypes and patient outcome, it is important to understand how LSR cellular localization mediates its functions. We conducted localization studies, evaluated DNA binding, and examined the effects of nuclear LSR in cells, xenografts, and clinical specimens. We found LSR within the membrane, cytoplasm, and the nucleus of breast cancer cells representing multiple intrinsic subtypes. Chromatin immunoprecipitation (ChIP) showed direct binding of LSR to DNA, and sequence analysis identified putative functional motifs and post-translational modifications of the LSR protein. While neither overexpression of transcript variants, nor pharmacological manipulation of post-translational modification significantly altered localization, inhibition of nuclear export enhanced nuclear localization, suggesting a mechanism for nuclear retention. Co-immunoprecipitation and proximal ligation assays indicated LSR-pericentrin interactions, presenting potential mechanisms for nuclear-localized LSR. The clinical significance of LSR was evaluated using data from over 1,100 primary breast tumors, which showed high LSR levels in basal-like tumors and tumors from African-Americans. In tumors histosections, nuclear localization was significantly associated with poor outcomes. Finally, in vivo xenograft studies revealed that basal-like breast cancer cells that over-express LSR exhibited both membrane and nuclear localization, and developed tumors with 100% penetrance, while control cells lacking LSR developed no tumors. These results show that nuclear LSR alters gene expression and may promote aggressive cancer phenotypes.

LSR Antibody Therapy Inhibits Ovarian Epithelial Tumor Growth by Inhibiting Lipid Uptake

“…However, the inhibitory effect of anti-hLSR mAb (#1-25) in vitro was not as intense as its effect in vivo. In breast cancer, a relationship between angiogenesis and nuclear-localized LSR has been reported (38). We targeted and analyzed membrane-localized LSR; however, downstream effects of LSR might involve angiogenesis, and our anti-LSR mAb (#1-25) might also inhibit this process in vivo.…”

Prognostic significance of Daxx NCR (Nuclear/Cytoplasmic Ratio) in gastric cancer

“…Previous studies have not made a connection between the Daxx nuclear/cytoplasmic expression ratio and GC, and this is the first study of its type to use Daxx IHC in clinical gastric carcinoma tissue. Numerous previous studies have shown that protein subcellular localization can be closely related to tumor progression. In this study, we found that the subcellular localization of Daxx in cells is complex, because it is expressed in both the nucleus and the cytoplasm.…”

“…It is well known that a protein's subcellular locations may be associated with different functions. In fact, numerous studies have shown that protein subcellular localization can be associated with functions that are closely related to tumor progression .…”

Genetic Aberration Analysis in Thai Colorectal Adenoma and Early-Stage Adenocarcinoma Patients by Whole-Exome Sequencing

“…The progression of normal epithelial cells to CRC involves multiple gene mutations within several signaling pathways, such as the Wnt signaling pathway, MAPK signaling pathway, PI3K signaling pathway, TGFβ signaling pathway, and p53 signaling pathway [11]. While APC, CTNNB1, LSR, TOPORS, KLF5, IGF1 and SOX9 are related to Wnt signaling pathways, KRAS and BRAF are involved in RAS signaling pathways [54,55,56,57,58,59,60]. This indicates that the abnormalities of proliferative pathways may crucial in early colorectal cancer development.…”