Chiaki Hayashi1, Kiyoshi Takagi1, Ai Sato1, Mio Yamaguchi1, Hiroyuki Minemura1, Yasuhiro Miki2,3, Narumi Harada-Shoji4, Minoru Miyashita4, Hironobu Sasano2,5, Takashi Suzuki6. 1. Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan. 2. Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan. 3. Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan. 4. Deparment Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan. 5. Department of Pathology, Tohoku University Hospital, Sendai, Japan. 6. Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan. t-suzuki@patholo2.med.tohoku.ac.jp.
Abstract
BACKGROUND: D-2-hydroxyglutarate dehydrogenase (D2HGDH) catalyzes D-2-hydroxyglutarate to α-ketoglutarate and is involved in the regulation of cellular energy and biosynthetic intermediates. Previously, D2HGDH was reported to decrease 2-hydroxyglutarate level in breast carcinoma cells, but no other report has examined D2HGDH in breast carcinoma, and its significance remains unknown. METHODS: We first immunolocalized D2HGDH in 224 invasive breast carcinomas and evaluated its clinicopathological significance. We next examined associations between gene expression of D2HGDH and α-ketoglutarate-dependent dioxygenases in 23 breast carcinoma tissues using the gene expression profile data. Finally, we examined the effects of D2HGDH on the proliferation in three breast carcinoma cells. RESULTS: D2HGDH immunoreactivity was detected in 49% of invasive breast carcinomas, and the immunohistochemical D2HGDH status was positively associated with histological grade, HER2 and Ki-67, while it was inversely associated with estrogen receptor. Moreover, it was significantly associated with worse prognosis of the breast cancer patients, and it turned out to be an independent prognostic factor for both the disease-free and breast cancer-specific survival in these patients. Gene expression profile data revealed that D2HGDH expression was positively associated with the expression of 6 α-ketoglutarate-dependent dioxygenases (KDM3A, PLOD1, EGLN2, ALKBH1, ASPH and ALKBH7). Consequent in vitro experiments demonstrated that D2HGDH overexpression significantly increased the cell proliferation activity of MCF-7, T47D and MDA-MB-231 cells. CONCLUSION: These results suggest that D2HGDH plays an important role in the growth of breast carcinoma, possibly through regulating functions of α-ketoglutarate-dependent dioxygenases, and that D2HGDH status is a potent worse prognostic factor in breast cancer patients.
BACKGROUND: D-2-hydroxyglutarate dehydrogenase (D2HGDH) catalyzes D-2-hydroxyglutarate to α-ketoglutarate and is involved in the regulation of cellular energy and biosynthetic intermediates. Previously, D2HGDH was reported to decrease 2-hydroxyglutarate level in breast carcinoma cells, but no other report has examined D2HGDH in breast carcinoma, and its significance remains unknown. METHODS: We first immunolocalized D2HGDH in 224 invasive breast carcinomas and evaluated its clinicopathological significance. We next examined associations between gene expression of D2HGDH and α-ketoglutarate-dependent dioxygenases in 23 breast carcinoma tissues using the gene expression profile data. Finally, we examined the effects of D2HGDH on the proliferation in three breast carcinoma cells. RESULTS: D2HGDH immunoreactivity was detected in 49% of invasive breast carcinomas, and the immunohistochemical D2HGDH status was positively associated with histological grade, HER2 and Ki-67, while it was inversely associated with estrogen receptor. Moreover, it was significantly associated with worse prognosis of the breast cancer patients, and it turned out to be an independent prognostic factor for both the disease-free and breast cancer-specific survival in these patients. Gene expression profile data revealed that D2HGDH expression was positively associated with the expression of 6 α-ketoglutarate-dependent dioxygenases (KDM3A, PLOD1, EGLN2, ALKBH1, ASPH and ALKBH7). Consequent in vitro experiments demonstrated that D2HGDH overexpression significantly increased the cell proliferation activity of MCF-7, T47D and MDA-MB-231 cells. CONCLUSION: These results suggest that D2HGDH plays an important role in the growth of breast carcinoma, possibly through regulating functions of α-ketoglutarate-dependent dioxygenases, and that D2HGDH status is a potent worse prognostic factor in breast cancer patients.
Authors: Ashley Davidson; Stephen Chia; Robert Olson; Alan Nichol; Caroline Speers; Andy J Coldman; Chris Bajdik; Ryan Woods; Scott Tyldesley Journal: CMAJ Open Date: 2013-11-07
Authors: M Elizabeth H Hammond; Daniel F Hayes; Mitch Dowsett; D Craig Allred; Karen L Hagerty; Sunil Badve; Patrick L Fitzgibbons; Glenn Francis; Neil S Goldstein; Malcolm Hayes; David G Hicks; Susan Lester; Richard Love; Pamela B Mangu; Lisa McShane; Keith Miller; C Kent Osborne; Soonmyung Paik; Jane Perlmutter; Anthony Rhodes; Hironobu Sasano; Jared N Schwartz; Fred C G Sweep; Sheila Taube; Emina Emilia Torlakovic; Paul Valenstein; Giuseppe Viale; Daniel Visscher; Thomas Wheeler; R Bruce Williams; James L Wittliff; Antonio C Wolff Journal: Arch Pathol Lab Med Date: 2010-07 Impact factor: 5.534
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