LRP1B: A Giant Lost in Cancer Translation

Abstract

Low-density lipoprotein receptor-related protein 1B (LRP1B) is a giant member of the LDLR protein family, which includes several structurally homologous cell surface receptors with a wide range of biological functions from cargo transport to cell signaling. LRP1B is among the most altered genes in human cancer overall. Found frequently inactivated by several genetic and epigenetic mechanisms, it has mostly been regarded as a putative tumor suppressor. Still, limitations in LRP1B studies exist, in particular associated with its huge size. Therefore, LRP1B expression and function in cancer remains to be fully unveiled. This review addresses the current understanding of LRP1B and the studies that shed a light on the LRP1B structure and ligands. It goes further in presenting increasing knowledge brought by technical and methodological advances that allow to better manipulate LRP1B expression in cells and to more thoroughly explore its expression and mutation status. New evidence is pushing towards the increased relevance of LRP1B in cancer as a potential target or translational prognosis and response to therapy biomarkers.

Whole-exome sequencing analysis identifies distinct mutational profile and novel prognostic biomarkers in primary gastrointestinal diffuse large B-cell lymphoma

“…In chronic lymphocytic leukaemia (CLL), IGLL5 mutations were associated with a trend towards decreased overall gene expression, and patients bearing IGLL5 mutations were suggestive for the low-risk of CLL [ 35 ], which to some extent, was consistent to our result showing that IGLL5 mutated pGI-DLBCL patients had a better OS. On the other hand, LRP1B is giant membrane molecule that is among the most altered genes in human malignancies [ 36 ]. Functional studies have confirmed that LRP1B expression in cancer cells could reduce in vitro cell proliferation and migration abilities, and also suppress in vivo tumorigenicity in mouse models [ 37 – 40 ].…”

Analysis of copy number alterations in bladder cancer stem cells revealed a prognostic role of LRP1B

“…LRP1B , member of the LDL receptor family, is a large gene located on chromosome 2q, containing more than 91 exons and spanning over 500 kb. The related protein is 4599 amino acids long [ 21 ] and it is involved in a large functional spectrum, ranging from receptor-mediated endocytosis, lipoprotein trafficking, transportation of nutrients and vitamins, developmental processes to cellular signaling [ 22 ]. LRP1B is one of the most altered genes in human cancer overall [ 22 ] and its role has been closely related to cancer progression.…”

“…The related protein is 4599 amino acids long [ 21 ] and it is involved in a large functional spectrum, ranging from receptor-mediated endocytosis, lipoprotein trafficking, transportation of nutrients and vitamins, developmental processes to cellular signaling [ 22 ]. LRP1B is one of the most altered genes in human cancer overall [ 22 ] and its role has been closely related to cancer progression. LRP1B gene was identified as commonly inactivated in non-small-cell lung cancer cell lines and its inactivation by several genetic and epigenetic mechanisms has been frequently reported in multiple tumor types [ 22 ], corroborating its proposed tumor suppressor function.…”

“…LRP1B is one of the most altered genes in human cancer overall [ 22 ] and its role has been closely related to cancer progression. LRP1B gene was identified as commonly inactivated in non-small-cell lung cancer cell lines and its inactivation by several genetic and epigenetic mechanisms has been frequently reported in multiple tumor types [ 22 ], corroborating its proposed tumor suppressor function. Recently, LRP1B association with tumor mutational burden and immunotherapy efficacy has been confirmed in lung and hepatocellular carcinomas, revealing the gene mutational status as a potential biomarker for immune check-point inhibitors (ICI) treatment response, through mast cells activation and infiltration in tumor tissues [ 23 , 24 ].…”

ALK-Positive Anaplastic Large-Cell Lymphoma in a Patient with Chronic Lymphocytic Leukemia: A Case Report and Literature Review

“…LRP1B is a putative tumor suppressor gene, and its mutation status has been found to be associated with enhanced cell proliferation and colony formation in various cancers. 26 In CLL, whole exome analysis showed that LRP1B mutation affected 5% of the patients, but its role is not fully understood. 27 …”