Nrh L11R single nucleotide polymorphism, a new prediction biomarker in breast cancer, impacts endoplasmic reticulum-dependent Ca2+ traffic and response to neoadjuvant chemotherapy

Abstract

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 IP3R1 Ca2+ channels in the former case. Collectively, our data show that cells expressing the Nrh-R isoform are more prone to death triggered by Ca2+ 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 IP3R1/Nrh complex as a potential therapeutic target in the context of breast cancer.

Causal effects and metabolites mediators between immune cell and risk of breast cancer: a Mendelian randomization study

“…Moreover, SNPs may influence the response of patients with BC to treatment. Some SNPs could affect the activity of drug-metabolizing enzymes, thus impacting drug concentrations and efficacy in vivo, ultimately affecting treatment effects and prognosis for patients with BC Frontiers in Genetics frontiersin.org (Noguchi et al, 2009;Duong et al, 2023;Oliva et al, 2023). These genes as mentioned, which could be influenced by SNPs and had an impact on the pathogenesis and treatment of BC, include noncoding genes and genes encoding protein, such as those in our research.…”

Bcl-B: an “unknown” protein of the Bcl-2 family

“…For example, a BCL2L10 single nucleotide polymorphism (rs2231292, Leu11Arg), which is predicted to be a biomarker of a favorable outcome, has been observed in patients with breast and rectal cancer. It leads to disturbance of the interactions between BCL2L10 and IP3R that, in turn, facilitates Ca 2+ release from the ER and activation of Ca 2+ -dependent cell death [ 72 , 73 ]. Additionally, patients with this BCL2L10 polymorphism have a diminished risk of the development de novo MDS [ 74 ].…”