In1-ghrelin splicing variant is associated with reduced disease-free survival of breast cancer patients and increases malignancy of breast cancer cells lines.

Rincon-Fernandez, DavidCuller, Michael DTsomaia, NatiaMoreno-Bueno, GemaLuque, Raul MGahete, Manuel DCastaño, Justo P2023-01-252023-01-252017-12-14Rincón-Fernández D, Culler MD, Tsomaia N, Moreno-Bueno G, Luque RM, Gahete MD, et al. In1-ghrelin splicing variant is associated with reduced disease-free survival of breast cancer patients and increases malignancy of breast cancer cells lines. Carcinogenesis. 2018 Mar 8;39(3):447-457http://hdl.handle.net/10668/11942Ghrelin gene generates several variants that regulate multiple pathophysiological functions, including tumor-related processes. In1-ghrelin is a splicing variant that was previously shown to be overexpressed in breast cancer (BCa), where it correlated with proliferation markers; however, its possible association with clinical outcome of BCa patients and underlying mechanisms are still unknown. To address this issue, expression levels and clinical associations of In1-ghrelin were analyzed in a cohort of 117 BCa samples. Additionally, a battery of cellular and molecular assays was implemented using two BCa cell lines (MCF-7 and MDA-MB-231), wherein the role of In1-ghrelin on proliferation, migration, dedifferentiation and signaling pathways was explored. The results generated revealed that high expression of In1-ghrelin in BCa samples was associated with lymph node metastasis and reduced disease-free survival. Indeed, In1-ghrelin overexpression stimulated proliferation and migration in MCF-7 and MDA-MB-231 cells. Similar results were found by treating MDA-MB-231 and MCF-7 with In1-ghrelin-derived peptides. Conversely, In1-ghrelin silencing decreased proliferation and migration capacities of MDA-MB-231. Furthermore, In1-ghrelin (but not ghrelin) overexpression increased the capacity to form mammospheres in both cell lines. These effects could be associated with activation of MAPK-ERK, Jag1/Notch, Wnt/β-catenin and/or TGF-β1 pathways. Altogether, our data indicate that In1-ghrelin could play relevant functional roles in the regulation of BCa development and progression and may provide insights to identify novel biomarkers and new therapeutic approaches for this pathology.enGhrelinKaplan-Meier estimateMiddle agedProtein isoformsAdultAgedBreast neoplasmsCarcinoma, ductal, breastCell line, tumorDisease-free survivalFemaleHumansIn1-ghrelin splicing variant is associated with reduced disease-free survival of breast cancer patients and increases malignancy of breast cancer cells lines.research article29272342open accessCarcinoma ductal de mamaFemeninoLínea celular tumoralNeoplasias de la mamaSupervivencia sin enfermedad10.1093/carcin/bgx1461460-2180https://academic.oup.com/carcin/article-pdf/39/3/447/24273439/bgx146.pdf