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Investigator

Tatsuhiko Imaoka

Director · National Institutes for Quantum Science and Technology, Department of Radiation Effects Research, Institute for Radiological Science

About

Papers

Susceptibility of Brca1(L63X/+) rat to ovarian reserve dissipation by chemotherapeutic agents to breast cancer

AbstractBRCA1 is one of the causative genes for hereditary breast and ovarian cancer syndrome with a high risk of early‐onset breast cancer. Whereas olaparib (OLA), an inhibitor of poly‐ADP‐ribose polymerase, has been applied as adjuvant therapy to those cancer patients, its effect on ovarian reproductive function remains unelucidated. Recently, a rat model (MUT; Brca1(L63X/+) mutation) mimicking a human BRCA1 pathogenic variant has been established. Using this model, we evaluated the effects of OLA on ovarian reproductive function in comparison with the wild‐type (WT) rats. MUT showed a significantly reduced number of primordial follicles and subfertility in accordance with aging. Oxidative stress was significantly elevated in the young MUT granulosa cells (GCs) accompanied by increased mTOR but decreased PTEN signals. OLA administration in MUT further decreased primordial follicles, with gene set enrichment analysis, indicating upregulated DNA repair pathways. Furthermore, a combination of OLA and cyclophosphamide (CPA) induced empty primordial follicles, recognized as CPA‐induced severe ovarian toxicity. Whereas OLA + CPA caused greater reduction in primordial follicles both in MUT and WT in comparison with CPA alone, MUT ovaries were more susceptible to oxidative stress, potentially depleting primordial follicles via activation of GCs and inducing oocyte death due to accumulated DNA damage by OLA treatment. Our findings in this preclinical model underscore the importance of evaluating ovarian reserve prior to chemotherapy by performing reproductive consultation with female patients with BRCA1 pathogenic variants.

83Works

1Papers

3Collaborators

Neoplasms, Radiation-InducedGenes, Tumor SuppressorBreast NeoplasmsMammary Neoplasms, ExperimentalFerroptosisLung NeoplasmsGenetic Predisposition to Disease

Positions

2024–

Director

National Institutes for Quantum Science and Technology · Department of Radiation Effects Research, Institute for Radiological Science

2019–

Team Leader (Group Leader until 2022)

National Institutes for Quantum Science and Technology · Quantum Cancer Science Team, Institute for Quantum Life Science

2023–

Group Leader

National Institutes for Quantum Science and Technology · Biomarker Research Group, Department of Radiation Effects Research, Institute for Radiological Science

2021–

Group Leader

National Institutes for Quantum Science and Technology · Stem Cells and Effect Modifiers Research Group, Department of Radiation Effects Research, National Institute of Radiological Sciences, Quantum Medical Science Directorate

2016–

Team Leader (Group Leader since 2019)

National Institutes for Quantum Science and Technology · Stem Cells and Cancer Research Team, Department of Radiation Effects Research, National Institute of Radiological Sciences

2011–

Team Leader

National Institute of Radiological Sciences · Radiobiology Research Team, Radiobiology for Children's Health Program, Research Center for Radiation Protection

2008–

Senior Researcher

National Institute of Radiological Sciences · Experimental Radiobiology for Children's Health Rearch Group, Research Center for Radiation Protection

2006–

Researcher

National Institute of Radiological Sciences · Experimental Radiobiology for Children's Health Research Group, Research Center for Radiation Protection

2002–

Reseaecher

National Institute of Radiological Sciences · Low Dose Radiation Effects Research Project 2nd Team, Research Center for Radiation Safety

2000–

Visiting Scientist

University of Cincinnati · Nelson Horseman Lab, Department of Molecular and Cellular Physiology, School of Medicine

Education

2002

Ph.D.

The University of Tokyo · Department of Biological Sciences, Graduate School of Science

1999

M.Sc.

The University of Tokyo · Laboratory of Endocrinology, Department of Biological Sciences, Graduate School of Science

1997

B.Sc. (Zoology)

The University of Tokyo · School of Science

1995

The University of Tokyo · Natural Sciences I, College of Arts and Sciences

1993

Azabu High School

Country

Links & IDs

0000-0003-1507-585X