Biology subjects

Toi, M.

Publications and source records attributed to Toi, M..

8 recordsLinked to original sources

bioRxiv2026

BRCA2 loss triggers a downward spiral of genomic instability via ROS-dependent metabolic collapse

BRCA2 plays a central role in maintaining genome integrity through homologous recombination and replication-fork protection, yet the compensatory networks sustaining BRCA2-deficient cells remain unclear. Here we show BRCA2 enforces a homeostatic mechanism aligning mitochondrial respiration with DNA repair capacity in both cancer and non-cancer contexts. Genome-wide CRISPR screening identified glutathione metabolism and base-excision repair as the key compensatory networks sustaining BRCA2-deficient cells by detoxifying mitochondria-derived reactive oxygen species. BRCA2 loss provokes an acute mitochondrial ROS surge, causing 8-oxoguanine accumulation and a systemic metabolic crisis marked by NAD+ and glutathione depletion. PARP inhibitor targets DNA replication vulnerabilities, increasing the cellular requirement for BRCA2. The resulting oxidative burden primes cells for TP53-dependent apoptosis in G1 during olaparib treatment, which extends cytotoxicity beyond canonical S-phase stress. These findings indicate BRCA2 prevents metabolic flux from outpacing repair capacity, providing a rationale for combining PARP inhibition with redox modulation to enhance efficacy and overcome resistance. HighlightsO_LIAcute BRCA2 loss induces ROS and mitochondrial dysfunction creating a metabolic scar C_LIO_LIOxidative lesions drive PARP hyperactivation and precipitate a cellular NAD crisis C_LIO_LIPARP inhibitors provoke TP53-dependent apoptosis in G1 beyond replication stress in S phase C_LIO_LIGlutathione deficiency exacerbates bone marrow failure under BRCA2 depletion C_LIO_LIBRCA2 tightly couples mitochondrial redox homeostasis to genomic maintenance C_LI

cell biology↗

bioRxiv2026

CDK12/13 inhibitor, CTX-439, suppresses tumor growth and potentiates BCL-2 family blockade

CDK12 and CDK13 (CDK12/13) regulate transcription by phosphorylating Serine 2 (S2) of the C-terminal domain of RNA polymerase II and have been proposed as therapeutic targets in cancer. Here we report the development of CTX-439, a novel, orally bioavailable, ATP-competitive small-molecule CDK12/13 inhibitor. CTX-439 specifically inhibits S2 phosphorylation and downregulates many genes including those involved in DNA damage repair, thereby exerting a profound anti-cancer effect in vitro and in vivo including breast cancer PDX models. A CRISPR activation screen identified BCL-2 and BCL-xL, anti-apoptotic BCL-2 family members, as genes that when upregulated confer resistance to CTX-439. Simultaneous inhibition of BCL-2/BCL-xL and CDK12/13 rapidly induced apoptosis and significantly suppressed xenograft tumor growth. Mechanistically, CTX-439 downregulates MCL1 protein levels through transcriptional readthrough, shifting cell survival dependency to BCL-2 and BCL-xL. Our study provides novel insights into the anti-tumor effect of CDK12/13 inhibition and proposes a new combination therapy strategy with anti-apoptotic BCL-2 family inhibitors, which may improve therapeutic outcomes in cancer treatment.

cancer biology↗

bioRxiv2025

Gamma-aminobutyric acid treatment reduces estradiol-stimulated breast cancer cell growth and estradiol-induced breast tumorigenesis

Gamma-aminobutyric acid (GABA) is a non-protein amino acid and contained in various foods, such as fruits and vegetables. Although various health benefits of GABA have been reported, GABA seems to have unidentified functions. In this study, we first show increase in intracellular GABA level in GABA-treated breast cancer cell lines, MCF-7 and T-47D, in amino acid analyses and immunofluorescence. In our experimental condition, GABA treatment reduced estradiol-stimulated cell growth in these cell lines. In addition, we performed mouse early breast cancer induction model system to investigate GABA function in mammary dysplasia formation. In the results, GABA administration reduced dysplasia formation, suggesting that GABA prevents breast tumorigenesis. This study demonstrates a novel function of GABA to maintain normal breast tissues.

bioengineering↗

bioRxiv2023

Low albumin status accompanies multi-layered immunosuppressive phenotypes in metastatic breast cancer patients

Low albumin status is prevalent in advanced cancer patients, but the pathophysiology associated with this anomaly remains largely unexplored. To address this, we aim to search correlations of albumin levels with the transcriptome against peripheral blood mononuclear cells and the plasma metabolome within the same patients having metastatic breast cancers. We confirm that metastatic breast cancer patients exhibit low albumin levels in varying degrees without prominent systemic inflammation. Our data demonstrate that low albumin levels correlate with transcriptome signatures indicative of "neutrophil activation and T-cell down-regulation," an immunosuppressive phenotype. We also find that immunoregulatory metabolites, such as arginine, are reduced in plasma in an albumin-correlated manner, further corroborating systemic immunosuppression. These results are verified using a mouse model of breast cancer. We conclude that low albumin status in metastatic breast cancer patients accompanies immunosuppressive phenotypes, which is likely unfavorable for anti-cancer immunotherapy and thus can be a cause of unsuccessful treatment outcomes.

cancer biology↗

bioRxiv2023

Selective elimination of CD169+ macrophages in lymph nodes invaded by breast cancers

Breast cancer cells suppress the host immune system to efficiently invade the lymph nodes; however, the underlying mechanism remains incompletely understood. Here, we report that metastasized breast cancer cells selectively eliminate CD169+ lymph node sinus macrophages, an initiator of anti-cancer immunity, from the lymph nodes. The comparison between paired lymph nodes with and without metastasis from the same patients demonstrated that the number of CD169+ macrophages was reduced in metastatic lymph nodes, whereas the numbers of other major immune cell types were unaltered. We also detected the infiltration of CD169+ macrophages into metastasized cancer tissues depending on sections, suggesting that CD169+ macrophages were gradually eliminated after anti-cancer reactions. Furthermore, CD169+ macrophage elimination was prevalent in major breast cancer subtypes and correlated with breast cancer staging. Collectively, we propose that metastasized breast cancer cells dispel CD169+ macrophages from lymph nodes in a phased manner, disabling a critical step of anti-cancer immunity.

cancer biology↗

bioRxiv2023

Senescence triggers intracellular acidification and lysosomal alkalinization via ATP6AP2 attenuation in breast cancer cells

Several chemotherapy drugs induce the senescence of cancer cells; however, the mechanism underlying intracellular pH dysregulation in senescent cells remains unclear. Adenosine triphosphatase H+ transporting accessory protein 2 (ATP6AP2) plays a critical role in maintaining pH homeostasis in cellular compartments. We here report a new function of ATP6AP2 in senescent breast cancer cells induced by doxorubicin and abemaciclib treatment. ATP6AP2 expression was significantly downregulated in senescent cells, leading to aberrant pH levels that impaired lysosome function and caused immune response changes. The drugs caused cell cycle arrest and proliferation suppression through the upregulation of senescence-related genes. Additionally, senescent cells showed altered inflammatory and immune transcriptional profiles by reprogramming the senescence-associated secretory phenotype. These findings suggest that ATP6AP2-mediated pH regulation during therapy-induced senescence may be linked to immune changes in senescent cancer cells. These findings provide novel insights into understanding the cellular mechanisms underlying the response to anti-cancer drugs.

cancer biology↗

bioRxiv2022

Serum amyloid alpha 1-2 are not required for systemic inflammation in the 4T1 murine breast cancer model

Cancers induce the production of acute phase proteins such as serum amyloid alpha (SAA) in the liver and cause systemic inflammation. Despite the well-known coincidence of acute phase response and systemic inflammation, the direct roles of SAA proteins in systemic inflammation in the cancer context remains incompletely characterized, particularly in vivo. Here, we investigate the in vivo significance of SAA proteins in systemic inflammation in the 4T1 murine breast cancer model. 4T1 cancers elevate the expression of SAA1 and SAA2, the two major murine acute phase proteins in the liver. The elevation of Saa1-2 correlates with the up-regulation of immune cell-related genes including neutrophil markers. To examine this correlation in detail, we generate mice that lack Saa1-2 and investigate immune-cell phenotypes. RNA-seq experiments reveal that deletion of Saa1-2 does not strongly affect 4T1-induced activation of immune cell-related genes in the liver and bone marrow. Flow cytometry experiments demonstrate the dispensable roles of SAA1-2 in cancer-dependent neutrophil infiltration to the liver. This study clarifies the negligible contribution of SAA1-2 proteins in systemic inflammation in the 4T1 breast cancer model.

cancer biology↗

bioRxiv2019

Estrogen induces mammary ductal dysplasia.

Mammary ductal dysplasia is a phenotype observed in precancerous lesions and early-stage breast cancer. However, the mechanism of dysplasia formation remains elusive. Here we show, by establishing a novel dysplasia model system, that estrogen, a female hormone, has the potential to cause mammary ductal dysplasia. We injected estradiol (E2), the most active form of estrogen, daily into scid mice with a defect in nonhomologous end joining repair and observed dysplasia formation with cell proliferation at day 30. Moreover, we found that isoflavones inhibited E2-induced dysplasia formation. Our dysplasia model system provides insight into the mechanistic understanding of breast tumorigenesis, and the development of breast cancer prevention.

cancer biology↗