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

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

doi:10.18632/oncotarget.26369

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 (χ2 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. ALDH1high 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 ALDH1high cell viability as well as the formation of tumor-spheres by ALDH1high cells. GLO1 knockdown using specific siRNAs also suppressed ALDH1high cell viability, and both TLSC702 and GLO1 siRNA induced apoptosis in ALDH1high 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.

Highlights

Breast cancer is the most commonly occurring cancer in women worldwide, with 2.5 million new cases (30% of all cancers in women) and 0.4 million cancerrelated deaths (14% of all cancer deaths in women) reported in 2017 [1]
Because Glo1 amplification often occurs in gastric [22] and liver cancers [25], we examined the alterations in copy number and mutations in Glo1 in breast cancer tissue
Our results revealed that Glyoxalase 1 (GLO1) inhibition using TLSC702 or siRNA suppressed ALDH1high cell viability and induced apoptosis (Figures 4 and 5)

Summary

Introduction

Breast cancer is the most commonly occurring cancer in women worldwide, with 2.5 million new cases (30% of all cancers in women) and 0.4 million cancerrelated deaths (14% of all cancer deaths in women) reported in 2017 [1]. Based on its receptor status, breast cancer is traditionally categorized as ER-positive, PgR-. Www.oncotarget.com positive, HER2-positive, or triple-negative (ER-negative, PgR-negative, HER2-negative) (TNBC). Breast cancer is classified into subtypes distinguished based on differences in their gene expression patterns (PAM50), including normal-like, luminal A, luminal B, HER2enriched, claudin-low and basal-like [2,3,4]. 70–80% of basal-like breast cancers reportedly fall into TNBC category [5]. Basal-like breast cancers have stemlike properties and a poor prognosis [6]. Identification and development of novel therapeutic targets for basal-like tumors are much needed

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Results

Conclusion