Glyoxalase 1 gene is highly expressed in basal-like human breast cancers and contributes to survival of ALDH1-positive breast cancer stem cells

Tamori, Shoma; Nozaki, Yuka; Motomura, Hitomi; Nakane, Hiromi; Katayama, Reika; Onaga, Chotaro; Kikuchi, Eriko; Shimada, Nobuyoshi; Suzuki, Yuhei; Noike, Mei; Hara, Yasushi; Sato, Keiko; Sato, Tsugumichi; Yamamoto, Keiji; Hanawa, Takehisa; Imai, Misa; Ryo, Akihide; Yoshimori, Atsushi; Takasawa, Ryoko; Tanuma, Sei Ichi; Akimoto, Kazunori

doi:10.18632/oncotarget.26369

Cited by 34 publications

(85 citation statements)

References 65 publications

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“…This could be due to the smaller number of patients within the TNBC cohort (i.e., 40 patients). In comparison to some protein targets, we noted that ALDH1A3 was significantly associated with worse outcomes in basal-like breast cancers, as has been reported previously [124]. Notably, DANCR and NRAD1 were associated with higher hazard ratios than other potential protein targets assessed (e.g., CSC markers, c-Myc).…”

Section: Therapeutic Targetssupporting

confidence: 85%

The Missing Lnc: The Potential of Targeting Triple-Negative Breast Cancer and Cancer Stem Cells by Inhibiting Long Non-Coding RNAs

Brown

Wasson

Marcato

2020

Cells

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Treatment decisions for breast cancer are based on staging and hormone receptor expression and include chemotherapies and endocrine therapy. While effective in many cases, some breast cancers are resistant to therapy, metastasize and recur, leading to eventual death. Higher percentages of tumor-initiating cancer stem cells (CSCs) may contribute to the increased aggressiveness, chemoresistance, and worse outcomes among breast cancer. This may be particularly true in triple-negative breast cancers (TNBCs) which have higher percentages of CSCs and are associated with worse outcomes. In recent years, increasing numbers of long non-coding RNAs (lncRNAs) have been identified as playing an important role in breast cancer progression and some of these have been specifically associated within the CSC populations of breast cancers. LncRNAs are non-protein-coding transcripts greater than 200 nucleotides which can have critical functions in gene expression regulation. The preclinical evidence regarding lncRNA antagonists for the treatment of cancer is promising and therefore, presents a potential novel approach for treating breast cancer and targeting therapy-resistant CSCs within these tumors. Herein, we summarize the lncRNAs that have been identified as functionally relevant in breast CSCs. Furthermore, our review of the literature and analysis of patient datasets has revealed that many of these breast CSC-associated lncRNAs are also enriched in TNBC. Together, this suggests that these lncRNAs may be playing a particularly important role in TNBC. Thus, certain breast cancer-promoting/CSC-associated lncRNAs could be targeted in the treatment of TNBCs and the CSCs within these tumors should be susceptible to anti-lncRNA therapy.

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Section: Therapeutic Targetssupporting

confidence: 85%

The Missing Lnc: The Potential of Targeting Triple-Negative Breast Cancer and Cancer Stem Cells by Inhibiting Long Non-Coding RNAs

Brown

Wasson

Marcato

2020

Cells

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“…Analysis of cancer genomics data. Gene expression data were downloaded from the cBioportal and analyzed as previously described (18,19,45). Briefly, the Molecular Taxonomy of Breast Cancer International Consortium dataset (METABRIC, n=2509) and The Cancer Genome Atlas (TCGA) provisional datasets for several cancers were downloaded from cBioPortal (46,47).…”

Section: Methodsmentioning

confidence: 99%

“…The MDA-MB 157 and MDA-MB 468 human basallike breast cancer cell lines were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA). The cells were then cultured as previously described (18,19).…”

Section: Methodsmentioning

confidence: 99%

“…WST-8 assay. WST-8 assays were performed as previously described (18,19). Briefly, cells (1×10 3 /well) were seeded into 96-well plates (Thermo Fisher Scientific, Waltham, MA, USA) and incubated for 24 h. Inhibitors were then added to the culture medium, and the cells were incubated for an additional 7 days, after which cell viability was assessed using Cell Count Reagent SF (Nacalai tesque, Kyoto, Japan).…”

Section: Methodsmentioning

confidence: 99%

“…Tumor-sphere culture. Tumor-spheres were grown as previously described (18,19). Briefly, cells (1×10 3 /well) were seeded into 96well ultralow attachment plates (Greiner Bio-One, Kremsmünster, Austria) and incubated for 24 h. Cells were cultured for 6 days while being treated with inhibitors.…”

Section: Methodsmentioning

confidence: 99%

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High Expression of c-Met, PKCλ and ALDH1A3 Predicts a Poor Prognosis in Late-stage Breast Cancer

et al. 2019

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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 ALDH1 high 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-Met high PKCλ high ALDH1A3 high have a poorer prognosis than patients with c-Met low PKCλ low ALDH1A3 low. Foretinib and auranofin suppressed cell viability and tumor-sphere formation by ALDH1 high 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. Breast cancer is the second most frequently diagnosed cancer worldwide, and the most commonly occurring cancer among women, with 2.09 million new cases (24.2% of all cancers in women) and 0.6 million cancer-related deaths annually (1). Breast cancers are classified based on their gene expression pattern (PAM 50) into at least six subtypes, including normallike, luminal A, luminal B, HER2-enriched, claudin-low and basal-like (2-5). Among these, basal-like breast cancers have stem-like properties and a poor prognosis (4). Nonetheless, the prognosis for breast cancer patients is good overall, though it is significantly poorer for patients with late-stage tumors (stage III or IV) (6). This is in large part because late-stage breast cancers are often resistant to standard medical treatments, such as conventional surgery, chemotherapy, and radiotherapy, which is reflected in their recurrence and metastasis (6). Consequently, the new pharmacological approach to managing late-stage breast cancers is greatly needed. Tumors are composed of populations of cancer cells and distinct cancer stem cells (CSCs), which are largely undifferentiated tumorigenic cells that exhibit such stem-like properties as self-renewal and multipotency (7, 8). Most CSCs are resistant to conventional chemo-and radiotherapies, and the development of targeted therapies against CSCs is very much needed to improve clinical outcomes. CSCs within breast tumors can be identified based on their expression of CD44, CD24 and aldehyde dehydrogenase 1 (ALDH1) (9, 10). ALDH1 is an enzyme that converts aldehydes to carboxylic acids and is abundant in normal stem/progenitor cells, and various CSCs, including those in breast cancers (9, 11). Among the ALDH1 gene family, ALDH1A1 and ALDH1A3 are known to be CSC markers in several cancers (12-17). In particular, ALDH1A3 reportedly contributes significantly to the ALDH1 activity detected in breast cancer cells, and its expression correlates significantly with cancer...

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Crystal structures of human glyoxalase I and its complex with TLSC702 reveal inhibitor binding mode and substrate preference

et al. 2022

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Human glyoxalase I (hGLO I) is an enzyme for detoxification of methylglyoxal (MG) and has been considered an attractive target for the development of new anticancer drugs. In our previous report, the GLO I inhibitor TLSC702 induced apoptosis in tumor cells. Here, we determined the crystal structures of hGLO I and its complex with TLSC702. In the complex, the carboxyl O atom of TLSC702 is coordinated to Zn2+, and TLSC702 mainly shows van der Waals interaction with hydrophobic residues. In the inhibitor‐unbound structure, glycerol, which has similar functional groups to MG, was bound to Zn2+, indicating that GLO I can easily bind to MG. This study provides a structural basis to develop better anticancer drugs.

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Glyoxalase 1 gene is highly expressed in basal-like human breast cancers and contributes to survival of ALDH1-positive breast cancer stem cells

Cited by 34 publications

References 65 publications

The Missing Lnc: The Potential of Targeting Triple-Negative Breast Cancer and Cancer Stem Cells by Inhibiting Long Non-Coding RNAs

The Missing Lnc: The Potential of Targeting Triple-Negative Breast Cancer and Cancer Stem Cells by Inhibiting Long Non-Coding RNAs

High Expression of c-Met, PKCλ and ALDH1A3 Predicts a Poor Prognosis in Late-stage Breast Cancer

Crystal structures of human glyoxalase I and its complex with TLSC702 reveal inhibitor binding mode and substrate preference

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