Nrh L11R single nucleotide polymorphism, a new prediction biomarker in breast cancer, impacts endoplasmic reticulum-dependent Ca2+ traffic and response to neoadjuvant chemotherapy
In: ISSN: 2041-4889 ; Cell Death and Disease ; https://hal.science/hal-04185345 ; Cell Death and Disease, 2023, 14, pp.392. ⟨10.1038/s41419-023-05917-7⟩, 2023
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International audience ; Overexpression of Bcl-2 proteins such as Bcl2L10, also referred to as Nrh, is associated with resistance to therapy and poor survival in various cancers, including breast cancer, lung cancer, and leukemia. The single nucleotide polymorphism (SNP) of BCL2L10 in its BH4 domain at position 11 (BCL2L10 Leu11Arg, rs2231292), corresponding to position 11 in the Nrh open reading frame, is reported to lower resistance towards chemotherapy, with patients showing better survival in the context of acute leukemia and colorectal cancer. Using cellular models and clinical data, we aimed to extend this knowledge to breast cancer. We report that the homozygous status of the Nrh Leu11Arg isoform (Nrh-R) is found in 9.7-11% percent of the clinical datasets studied. Furthermore, Nrh-R confers higher sensitivity towards Thapsigargin-induced cell death compared to the Nrh-L isoform, due to altered interactions with IP 3 R1 Ca 2+ channels in the former case. Collectively, our data show that cells expressing the Nrh-R isoform are more prone to death triggered by Ca 2+ stress inducers, compared to Nrh-L expressing cells. Analysis of breast cancer cohorts revealed that patients genotyped as Nrh-R/Nrh-R may have a better outcome. Overall, this study supports the notion that the rs2231292 Nrh SNP could be used as a predictive tool regarding chemoresistance, improving therapeutic decision-making processes. Moreover, it sheds new light on the contribution of the BH4 domain to the anti-apoptotic function of Nrh and identifies the IP 3 R1/Nrh complex as a potential therapeutic target in the context of breast cancer.
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Nrh L11R single nucleotide polymorphism, a new prediction biomarker in breast cancer, impacts endoplasmic reticulum-dependent Ca2+ traffic and response to neoadjuvant chemotherapy
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Autor/in / Beteiligte Person: | Duong, Minh, Quang ; Gadet, Rudy ; Treilleux, Isabelle ; Borel, Stéphane ; Nougarède, Adrien ; Marcillat, Olivier ; Gonzalo, Philippe ; Mikaelian, Ivan ; Popgeorgiev, Nikolay ; Rimokh, Ruth ; Gillet, Germain ; Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL) ; Centre Léon Bérard Lyon -Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS) ; Centre Léon Bérard Lyon ; Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI) ; Direction de Recherche Technologique (CEA) (DRT (CEA)) ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA) ; Centre Hospitalier Universitaire de Saint-Etienne CHU Saint-Etienne (CHU ST-E) |
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Zeitschrift: | ISSN: 2041-4889 ; Cell Death and Disease ; https://hal.science/hal-04185345 ; Cell Death and Disease, 2023, 14, pp.392. ⟨10.1038/s41419-023-05917-7⟩, 2023 |
Veröffentlichung: | HAL CCSD ; Nature Publishing Group, 2023 |
Medientyp: | academicJournal |
DOI: | 10.1038/s41419-023-05917-7 |
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