title: LGR5 is a biomarker for stratification of HER-2 positive breast cancer patients and personalized treatment.
abstract: VEGFR and HER2 are both important transmembrane proteins associated with several types of cancer. Overexpression of these 2 proteins had long been thought to contribute to cancer progression and poor outcomes, thus, therapies targeting HER-2 and VEGFA signaling pathways have been applied in recent years. Herceptin is a HER-2 targeted antibody that being widely used for the management of HER-2 positive breast cancer, which demonstrate significant benefits in both the metastatic and adjuvant settings. However, acquired resistance develops in most treated patients despite treatment in as early as 10 months. Identification of subpopulations best suited for and most likely to respond to Herceptin is of utmost importance. We analyzed the signaling pathways of HER-2 and found that HER-2 shares a very similar downstream network with VEGFA, while LGR5 lies in the upstream of VEGFA and could promotes its expression through CTNNB1. This discovery suggests that the LGR5 directed VEGFA overexpression may activate downstream signals of HER-2 despite Herceptin treatment. Here, we hypothesized that in LGR5 overexpressing breast cancer cases, activation of VEGFA-VRGFR bypass may account for the resistance to HER-2 directed therapies. Concurrent inhibition of VEGFR might enhance Herceptin sensitivity and moreover reverse the resistant phenotype in HER-2 positive breast cancer. Thus, we proposed alternate regimens to increase the efficacy of Herceptin-based therapy. Nevertheless, wet lab experiments and clinical trials are still required.
authors.affiliation: Department of Anesthesiology, Second Xiangya Hospital, Central South University, Anesthesiology Research Institute, Central South University, Changsha, Hunan, China.
authors.forename: Chan
authors.initials: C
authors.lastname: Chen
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Jun-Mei
authors.initials: JM
authors.lastname: Xu
authors.forename: Yong
authors.initials: Y
authors.lastname: Han
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D008954:Models, Biological; D057285:Precision Medicine / Q000379:methods; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000068878:Trastuzumab; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; D043562:Receptors, G-Protein-Coupled; D000068878:Trastuzumab; D042461:Vascular Endothelial Growth Factor A; C116884:LGR5 protein, human; C467484:VEGFA protein, human; C508053:ERBB2 protein, human
keywords: AKT; CTNNB1; HER-2; IgG1; LGR5; MAPK; P27; PI3K; PTEN; RER; VEGFA; VEGFR; catenin (cadherin-associated protein), beta 1; cyclin-dependent kinase inhibitor 1B (p27, Kip1); immunoglobulin G 1; leucine-rich repeat containing G protein-coupled receptor 5; mitogen-activated protein kinase; phosphatase and tensin homolog; phosphoinositide-3-kinase; rough endoplasmic reticulum; v-akt murine thymoma viral oncogene; v-erb-b2 erythroblastic leukemia viral oncogene homolog 2; vascular endothelial growth factor A; vascular endothelial growth factor receptor