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Isoforms of IDH in breast carcinoma: IDH2 as a potent prognostic factor associated with proliferation in estrogen-receptor positive cases

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Abstract

Background

Isocitrate dehydrogenase (IDH) is an important enzyme that oxidatively decarboxylates isocitrate to α-ketoglutarate, and three isoforms (IDH1-3) have been identified. Overexpression and/or downregulation of IDH isoforms was reported in several human malignancies, suggesting importance of IDH in oncogenesis. However, significance of IDH isoforms remains largely unclear in the breast carcinoma.

Methods

We immunolocalized IDH1, IDH2 and IDH3α in 226 breast carcinomas and evaluated their clinical significance. Subsequently, we examined effects of IDH2 on proliferation in breast carcinoma cells.

Results

Immunoreactivity of IDH1-3α was detected in 53%, 38% and 41% of breast carcinomas, and the non-neoplastic epithelium was IDH1-positive, IDH2-negative and IDH3α-positive. IDH1 immunoreactivity was inversely associated with pathological T factor (pT) and Ki-67 in the breast carcinoma, while IDH3α immunoreactivity was not significantly associated with clinicopathological factors. IDH2 status was positively correlated with stage, pT, histological grade, HER2, Ki-67 and microvessel density. Moreover, IDH2 status was significantly associated with worse prognosis of the patients, and it turned out an independent prognostic factor for estrogen-receptor (ER) positive patients. These findings were more evident in the IDH1-negative / IDH2-positive/IDH3α-negative subgroup which is the opposite immunohistochemical IDH phenotype of normal mammary epithelium. In vitro studies demonstrated that RNA interference of IDH2 significantly decreased proliferation activity of T47D and SKBR-3 cells.

Conclusion

These results suggest that IDH2 is associated with an aggressive phenotype of breast carcinoma through increasing cell proliferation, different from IDH1 and IDH3α, and immunohistochemical IDH2 status is a potent prognostic factor especially in ER-positive breast cancer patients.

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Acknowledgements

This work was partly supported by JSPS KAKENHI Grant Number 19K09065 and 19K07410.

Author information

Authors and Affiliations

  1. Department of Pathology and Histotechnology, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan

    Hiroyuki Minemura, Kiyoshi Takagi, Ai Sato, Mio Yamaguchi, Chiaki Hayashi & Takashi Suzuki

  2. Department of Anatomic Pathology, Tohoku University, Sendai, Japan

    Yasuhiro Miki & Hironobu Sasano

  3. Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan

    Yasuhiro Miki

  4. Department of Breast and Endocrine Surgical Oncology, Graduate School of Medicine, Tohoku University, Sendai, Japan

    Narumi Harada-Shoji & Minoru Miyashita

  5. Department of Pathology, Tohoku University Hospital, Sendai, Japan

    Hironobu Sasano

Authors
  1. Hiroyuki Minemura
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  2. Kiyoshi Takagi
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  3. Ai Sato
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  10. Takashi Suzuki
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Contributions

HM performed immunohistochemical experiments and prepared the manuscript. KT contributed the experimental design and performed statistical analysis. AS performed in vitro experiments. MY, CH and YM gave skillful suggestions of immunohistochemistry and in vitro studies. NH-S and MM collected and managed clinical information of the patients. HS collected and managed pathological information and specimens examined. TS contributed the study conception and performed immunohistochemical evaluation.

Corresponding author

Correspondence to Takashi Suzuki.

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The authors declare that they have no conflict of interest.

Research involving Human participants and/or Animals

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethics Committee at Tohoku University Graduate School of Medicine and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required. This article does not contain any studies with animals performed by any of the authors.

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The design of this study is retrospective study and informed consent is not required.

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Minemura, H., Takagi, K., Sato, A. et al. Isoforms of IDH in breast carcinoma: IDH2 as a potent prognostic factor associated with proliferation in estrogen-receptor positive cases. Breast Cancer 28, 915–926 (2021). https://doi.org/10.1007/s12282-021-01228-x

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  • DOI: https://doi.org/10.1007/s12282-021-01228-x

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