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BACKGROUND/AIM We examined the inhibitory effects of both glyoxalase 1 (GLO 1) and protein kinase C (PKC)λ in aldehyde dehydrogenase 1 (ALDH1)-positive breast cancer stem cells (CSCs). MATERIALS AND METHODS Breast cancer genomics datasets (TCGA, n=593; METABRIC, n=1904) were downloaded and statistically analyzed. The effects of GLO 1 and PKCλ on trypan blue staining and tumor-sphere formation by ALDH1high cells derived from triple negative breast cancer (TNBC) and basal-like breast cancer were examined. RESULTS GLO 1high, PKCλhigh, and ALDH1A3high tumors were enriched in stage I/II/III/IV samples, associated with the HER2 and TNBC subtypes according to receptor status, and associated with the HER2-enriched and basal-like subtypes according to PAM50. Inhibition of either GLO 1 (TLSC702) or PKCλ (ANF) suppressed tumor-sphere formation and enhanced death in ALDH1high cells. TLSC702 also effectively inhibited tumor-sphere formation and induced death in PKCλ knockout ALDH1high cells. CONCLUSION GLO 1 and PKCλ are important for the survival of ALDH1-positive breast CSCs, and may represent potential therapeutic targets for the treatment of ALDH1-positive breast CSCs.

CD58 is an immune adhesion molecule on the cellular surface. It was previously found that a high expression of CD58 predicted a poor prognosis of patients with lower-grade gliomas. Therefore, the aim of this paper was to investigate the association between CD58 and breast cancer.CD58 gene expression data downloaded from cBioPortal was compared between the different subtypes of breast cancer. Clinical prognosis was examined using Kaplan-Meier analysis and multivariable Cox regression analysis. The association between CD58 expression and immune cell infiltration was estimated using the TIMER 2.0 web platform. Finally, the tumour sphere formation of aldehyde dehydrogenase 1 (ALDH1)CD58 mRNA was mainly enriched in claudin-low and basal-like subtypes. The high expression of CD58 predicted a good prognosis in patients with luminal A and luminal B breast cancer. This prediction may be due to the association of immune cell infiltration with CD58. Notably, patients with luminal A breast cancer with a high expression of CD58 in association with ALDH1A3 exhibited a good prognosis; however, this did not apply to patients with basal-like breast cancer. The in vitro experiments revealed that knockdown of CD58 inhibited the tumour sphere formation ability of ALDH1CD58 may function as a potential prognostic biomarker and therapeutic target in ALDH-positive basal-like cancer stem cells.

Background/Aim: Radiotherapy is one of the main treatments for estrogen receptor-positive (ER+) breast cancer. However, in some ER+ breast cancer cases, radiotherapy is insufficient to inhibit progression and there is a lack of markers to predict radiotherapy insensitivity. Solute carrier family 20 member 1 (SLC20A1) is a sodium/inorganic phosphate symporter, which has been proposed to be a viable prognostic marker for luminal A and B types of ER+ breast cancer. The present study examined the possibility of SLC20A1 as a novel biomarker for the prediction of radiotherapy efficiency. Patients and Methods: The Molecular Taxonomy of Breast Cancer International Consortium dataset was downloaded from cBioportal and the prognosis of patients with high SLC20A1 expression (SLC20A1high) was compared with that of patients with low SLC20A1 expression, without or with radiotherapy and tumor stages I, II, and III, using the Kaplan–Meier method and multivariate Cox regression analyses of disease-specific and relapse-free survival. Results: Patients in the SLC20A1high group with radiotherapy showed poor clinical outcomes in both luminal A and luminal B breast cancers. Furthermore, in luminal A breast cancer at tumor stage I, patients in the SLC20A1high group with radiotherapy also showed poor clinical outcomes. Therefore, these results suggest that radiotherapy is insufficient for patients in the SLC20A1high group for both luminal A and B types, and especially for the luminal A type at tumor stage I. Conclusion: SLC20A1 can be used as a prognostic marker for the prediction of the efficacy of radiotherapy for luminal A and luminal B breast cancers.

p62 (also known as sequestosome 1) is involved in cancer progression, and high expression of p62 indicates poor clinical outcome in several cancer types. However, the association between p62 gene expression and cancer stem cells (CSCs) in breast cancer subtypes remains unclear.In the present study, genomic datasets of primary breast cancer (The Cancer Genome Atlas, n=593; and Molecular Taxonomy of Breast Cancer International Consortium, n=2,509) were downloaded. p62 Expression was then examined in normal and breast cancer tissues derived from the same patients. Kaplan-Meier and multivariate Cox regression analyses were employed to evaluate disease-specific survival. Next, the effect on cell viability and in vitro tumor-sphere formation of p62 knockdown using targeted small interfering RNA was assessed by using cells with high activity of aldehyde dehydrogenase 1 (ALDH1Patients with normal-like, luminal A or luminal B breast cancer with p62p62 is potentially a prognostic marker and therapeutic target for ALDH1-positive luminal B breast CSCs.

Background/aim Co-expression of c-Met and ALDH1A3 indicates a poor prognosis in stage III-IV breast cancers and contributes to cell proliferation and tumor formation by ALDH1-positive breast CSCs. PKCλ is overexpressed and contributes to a poor prognosis in several cancers. Materials and methods A breast cancer genomics data set (METABRIC, n=2509) was downloaded and analyzed, as was the effect c-Met and PKCλ inhibitors on ALDH1high cell viability and tumor-sphere formation. Results c-Met expression correlates with expression of PKCλ in breast cancer. Stage III-IV breast cancer patients with c-Methigh PKCλhigh ALDH1A3high have a poorer prognosis than patients with c-Metlow PKCλlow ALDH1A3low Foretinib and auranofin suppressed cell viability and tumor-sphere formation by ALDH1high cells. These results suggest that c-Met and PKCλ are cooperatively involved in cancer progression and contribute to poor prognoses in breast cancer. Conclusion c-Met and PKCλ are potentially useful prognostic markers and therapeutic targets in late-stage breast cancer.

Cancer cells upregulate the expression levels of glycolytic enzymes in order to reach the increased glycolysis required. One such upregulated glycolytic enzyme is glyoxalase 1 (GLO 1), which catalyzes the conversion of toxic methylglyoxal to nontoxic S-D-lactoylglutathione. Protein kinase Cλ (PKCλ) is also upregulated in various types of cancer and is involved in cancer progression. In the present study, the association between enhanced glycolysis and PKCλ in breast cancer was investigated. In human breast cancer, high GLO 1 expression was associated with high PKCλ expression at the protein (P

// Shoma Tamori 1, 6 , Yuka Nozaki 1, 6 , Hitomi Motomura 1, 6 , Hiromi Nakane 1 , Reika Katayama 1 , Chotaro Onaga 1 , Eriko Kikuchi 1 , Nami Shimada 2 , Yuhei Suzuki 1 , Mei Noike 1 , Yasushi Hara 3 , Keiko Sato 4, 6 , Tsugumichi Sato 2, 6 , Kouji Yamamoto 5, 6 , Takehisa Hanawa 2, 6 , Misa Imai 8, 9 , Ryo Abe 3, 11 , Atsushi Yoshimori 10 , Ryoko Takasawa 2 , Sei-Ichi Tanuma 2, 7 and Kazunori Akimoto 1, 6 1 Department of Medicinal and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan 2 Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan 3 Research Institute for Biochemical Sciences, Tokyo University of Science, Chiba, Japan 4 Department of Information Sciences, Faculty of Science and Technology, Tokyo University of Science, Chiba, Japan 5 Department of Biostatistics, Yokohama City University, School of Medicine, Yokohama, Japan 6 Translational Research Center, Research Institute for Science and Technology, Tokyo University of Science, Chiba, Japan 7 Laboratory of Genomic Medicinal Science, Research Institute for Science and Technology, Tokyo University of Science, Chiba, Japan 8 Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan 9 Leading Center for the Development and Research of Cancer Medicine, Juntendo University School of Medicine, Tokyo, Japan 10 Institute for Theoretical Medicine, Inc., Kanagawa, Japan 11 Strategic Innovation and Research Center, Teikyo University, Tokyo, Japan Correspondence to: Kazunori Akimoto, email: akimoto@rs.tus.ac.jp Keywords: cancer stem cell; glyoxalase 1; breast cancer; the Warburg effect; target therapy Received: July 04, 2018 Accepted: November 01, 2018 Published: November 23, 2018 ABSTRACT Glyoxalase 1 (GLO1) is a ubiquitous enzyme involved in the detoxification of methylglyoxal, a cytotoxic byproduct of glycolysis that induces apoptosis. In this study, we found that GLO1 gene expression correlates with neoplasm histologic grade ( χ 2 test , p = 0.002) and is elevated in human basal-like breast cancer tissues. Approximately 90% of basal-like cancers were grade 3 tumors highly expressing both GLO1 and the cancer stem cell marker ALDH1A3 . ALDH1 high cells derived from the MDA-MB 157 and MDA-MB 468 human basal-like breast cancer cell lines showed elevated GLO1 activity. GLO1 inhibition using TLSC702 suppressed ALDH1 high cell viability as well as the formation of tumor-spheres by ALDH1 high cells. GLO1 knockdown using specific siRNAs also suppressed ALDH1 high cell viability, and both TLSC702 and GLO1 siRNA induced apoptosis in ALDH1 high cells. These results suggest GLO1 is essential for the survival of ALDH1-positive breast cancer stem cells. We therefore conclude that GLO1 is a potential therapeutic target for treatment of basal-like breast cancers.

c-Met is a receptor-type tyrosine kinase, which is involved in a wide range of cellular responses such as proliferation, motility, migration and invasion. It has been reported to be overexpressed in various cancers. However, the role of c-Met in breast cancer stem cells (CSCs) still remains unclear. We herein, show that c-Met expression is significantly elevated in Basal-like type of breast cancer in comparison with other subtypes. High expression of c-Met strongly correlated with the expression of two CSC markers, ALDH1A3 and CD133 in breast cancers. In addition, breast cancers at tumor stage III-IV expressing both c-Methigh and ALDH1A3high had poor prognosis. Furthermore, treatment with c-Met inhibitors (Crizotinib, Foretinib, PHA-665752 and Tivantinib) in MDA-MB157 cells with high c-Met protein expression resulted in significant suppression in cell viability, contrary to MDA-MB468 cells with low c-Met protein expression. These c-Met inhibitors also suppressed cell viability and tumor-sphere formation of ALDH1high breast cancer cells with high c-Met expression. These results suggest that c-Met in ALDH1 positive CSCs seems to play an important role in breast cancer repopulation. Therefore, we conclude that c-Met is a potential therapeutic target in ALDH1 positive breast CSCs.

Despite development of markers for identification of cancer stem cells, the mechanism underlying the survival and division of cancer stem cells in breast cancer remains unclear. Here we report that PKCλ expression was enriched in basal-like breast cancer, among breast cancer subtypes, and was correlated with ALDH1A3 expression (p = 0.016, χ2-test). Late stage breast cancer patients expressing PKCλhigh and ALDH1A3high had poorer disease-specific survival than those expressing PKCλlow and ALDH1A3low (p = 0.018, log rank test for Kaplan-Meier survival curves: hazard ratio 2.58, 95% CI 1.24-5.37, p = 0.011, multivariate Cox regression analysis). Functional inhibition of PKCλ through siRNA-mediated knockdown or CRISPR-Cas9-mediated knockout in ALDH1high MDA-MB 157 and MDA-MB 468 basal-like breast cancer cells led to increases in the numbers of trypan blue-positive and active-caspase 3-positive cells, as well as suppression of tumor-sphere formation and cell migration. Furthermore, the amount of CASP3 and PARP mRNA and the level of cleaved caspase-3 protein were enhanced in PKCλ-deficient ALDH1high cells. An Apoptosis inhibitor (z-VAD-FMK) suppressed the enhancement of cell death as well as the levels of cleaved caspase-3 protein in PKCλ deficient ALDH1high cells. It also altered the asymmetric/symmetric distribution ratio of ALDH1A3 protein. In addition, PKCλ knockdown led to increases in cellular ROS levels in ALDH1high cells. These results suggest that PKCλ is essential for cancer cell survival and migration, tumorigenesis, the asymmetric distribution of ALDH1A3 protein among cancer cells, and the maintenance of low ROS levels in ALDH1-positive breast cancer stem cells. This makes it a key contributor to the poorer prognosis seen in late-stage breast cancer patients.

Co-expression of c-Met and ALDH1A3 indicates a poor prognosis in stage III-IV breast cancers and contributes to cell proliferation and tumor formation by ALDH1-positive breast CSCs. PKCλ is overexpressed and contributes to a poor prognosis in several cancers.A breast cancer genomics data set (METABRIC, n=2509) was downloaded and analyzed, as was the effect c-Met and PKCλ inhibitors on ALDH1c-Met expression correlates with expression of PKCλ in breast cancer. Stage III-IV breast cancer patients with c-Metc-Met and PKCλ are potentially useful prognostic markers and therapeutic targets in late-stage breast cancer.

2020年度