Hidetaka Shima1,2, Kumiko Kida1,2, Shoko Adachi1,2, Akimitsu Yamada3,4,5, Sadatoshi Sugae1, Kazutaka Narui2, Yohei Miyagi6, Mayuko Nishi7, Akihide Ryo7, Soichiro Murata8, Hideki Taniguchi8, Yasushi Ichikawa9, Takashi Ishikawa10, Itaru Endo1. 1. Department of Gastroenterological Surgery, Yokohama City University, 3-9 Fukuura, Kanazawa-ward, Yokohama, Kanagawa, 236-0004, Japan. 2. Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, 4-57 Urafunecho, Minami-ward, Yokohama, Kanagawa, 232-0024, Japan. 3. Department of Gastroenterological Surgery, Yokohama City University, 3-9 Fukuura, Kanazawa-ward, Yokohama, Kanagawa, 236-0004, Japan. ayamada@yokohama-cu.ac.jp. 4. Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, 4-57 Urafunecho, Minami-ward, Yokohama, Kanagawa, 232-0024, Japan. ayamada@yokohama-cu.ac.jp. 5. Department of Breast Surgery, Chigasaki Municipal Hospital, 5-15-1, Honson, Chigasaki, Kanagawa, 253-0042, Japan. ayamada@yokohama-cu.ac.jp. 6. Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 2-3-2 Nakao, Asahi-ward, Yokohama, Kanagawa, 241-0815, Japan. 7. Department of Molecular Biodefense Research, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ward, Yokohama, Kanagawa, 236-0004, Japan. 8. Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ward, Yokohama, Kanagawa, 236-0004, Japan. 9. Department of Oncology, Yokohama City University, 3-9 Fukuura, Kanazawa-ward, Yokohama, Kanagawa, 236-0004, Japan. 10. Department of Breast Disease, Tokyo Medical University Hospital, 6-7-1 Nishi-shinjuku, Shinjuku-ward, Tokyo, 160-0023, Japan.
Abstract
PURPOSE: Aldehyde dehydrogenase1 (ALDH1) is widely accepted as a stem cell marker for normal breast as well as in breast cancer. Although the clinical impact of ALDH1 was observed in our previous study, we do not know how ALDH1 affects stem cell features resulting in worsening of prognosis in breast cancer. The purpose of this study is to explore ALDH1-related gene and its function on cancer stem cell (CSC). METHODS: In five cases of ALDH1-positive triple-negative breast cancer, mRNA expression profile was compared between ALDH1-positive and ALDH1-negative cells by Affymetrix microarray analysis after microdissection. Among the genes modulated in ALDH1-positive cells, we focused on H19, which encodes a long non-coding RNA, in this study. An in-vitro study was conducted with H19 siRNA in HCC1934 and iCSCL10A cell lines. The association of H19 with prognosis was examined in 180 breast cancer cases. RESULTS: Network analysis revealed the existence of five genes related with H19, including miR-103, miR-107, let-7, miR-29b-1, and Trx. In-vitro analysis showed that suppression of H19 using siRNA reduces sphere formation capacity in both HCC1934 and iCSCL10A cell lines. In clinical studies, H19 expression was associated with hormone negativity, tumor size, and nodal status. Patients with H19 expression had significantly poor disease-free survival (DFS) (26.3 vs. 64.8% at 5 years, p = 0.001) and overall survival (OS) (28.9 vs. 68.3% at 5 years, p = 0.004). The effect of H19 expression on prognosis was the most significant in triple-negative breast cancer compared to that in other subtypes (20.0 vs. 65.4% at 5 years DFS, p = 0.012, 20.0 vs. 69.2% at 5 years OS, p = 0.016). CONCLUSION: This study indicated that H19 was associated with stem cell phenotype in ALDH1-positive breast cancer. H19 regulates CSC and is associated with poor prognosis in breast cancer patients, particularly in triple-negative subtype.
PURPOSE: Aldehyde dehydrogenase1 (ALDH1) is widely accepted as a stem cell marker for normal breast as well as in breast cancer. Although the clinical impact of ALDH1 was observed in our previous study, we do not know how ALDH1 affects stem cell features resulting in worsening of prognosis in breast cancer. The purpose of this study is to explore ALDH1-related gene and its function on cancer stem cell (CSC). METHODS: In five cases of ALDH1-positive triple-negative breast cancer, mRNA expression profile was compared between ALDH1-positive and ALDH1-negative cells by Affymetrix microarray analysis after microdissection. Among the genes modulated in ALDH1-positive cells, we focused on H19, which encodes a long non-coding RNA, in this study. An in-vitro study was conducted with H19 siRNA in HCC1934 and iCSCL10A cell lines. The association of H19 with prognosis was examined in 180 breast cancer cases. RESULTS: Network analysis revealed the existence of five genes related with H19, including miR-103, miR-107, let-7, miR-29b-1, and Trx. In-vitro analysis showed that suppression of H19 using siRNA reduces sphere formation capacity in both HCC1934 and iCSCL10A cell lines. In clinical studies, H19 expression was associated with hormone negativity, tumor size, and nodal status. Patients with H19 expression had significantly poor disease-free survival (DFS) (26.3 vs. 64.8% at 5 years, p = 0.001) and overall survival (OS) (28.9 vs. 68.3% at 5 years, p = 0.004). The effect of H19 expression on prognosis was the most significant in triple-negative breast cancer compared to that in other subtypes (20.0 vs. 65.4% at 5 years DFS, p = 0.012, 20.0 vs. 69.2% at 5 years OS, p = 0.016). CONCLUSION: This study indicated that H19 was associated with stem cell phenotype in ALDH1-positive breast cancer. H19 regulates CSC and is associated with poor prognosis in breast cancerpatients, particularly in triple-negative subtype.
Authors: Jamie A Barr; Karen E Hayes; Tayvia Brownmiller; Abby D Harold; Rajaganapathi Jagannathan; Paul R Lockman; Saleem Khan; Ivan Martinez Journal: Sci Rep Date: 2019-03-06 Impact factor: 4.379