Correlation between c-Met and ALDH1 contributes to the survival and tumor-sphere formation of ALDH1 positive breast cancer stem cells and predicts poor clinical outcome in breast cancer

Yuka Nozaki,Shota Shiina,Yasushi Hara,Yuka Onodera,Reika Katayama,Kazunori Akimoto,Masahiro Inada,Kei Tamura,Sei-Ichi Tanuma,Daichi Kodama,Keiko Sato,Ryo Abe,Nariyoshi Shinomiya,Ryoko Takasawa,Shoma Tamori,Atsushi Yoshimori,Hiromi Nakane,Osamu Minamishima,Makoto Abe

doi:10.18632/genesandcancer.148

Abstract

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.

Highlights

Breast cancer is one of the most common cancers occurring in women worldwide with 1.7 million new cases (25.2% of all cancers in women) and 0.5 million-cancer deaths (14.7% of all cancer death in women) according to an estimate from the International Agency for Research on Cancer (IARC) [1]
C-Met inhibitors suppressed the viability and tumor-sphere formation of ALDH1high cells. These results suggest that c-Met is essential for the viability and tumor formation of ALDH1 positive breast cancer stem cells (CSCs)
As c-Met+ tumor lesions were higher in tumor stage III-IV, in contrast with stage 0, I, and II, we focused to analyze the relationship between c-Met gene expression and CSC markers in breast cancer subtypes at tumor stage III-IV. c-Met mRNA was found to be enriched in Basal-like type in comparison with other subtypes at stage III and IV (Figure 2A)

Summary

Introduction

Breast cancer is one of the most common cancers occurring in women worldwide with 1.7 million new cases (25.2% of all cancers in women) and 0.5 million-cancer deaths (14.7% of all cancer death in women) according to an estimate from the International Agency for Research on Cancer (IARC) [1]. Breast cancer has been widely classified based on specific gene expression signature and receptor status. Based on PAM50 gene expression signature, breast cancer is categorized into six ‘’intrinsic’’ subtypes namely, Luminal A, Luminal B, HER2-enriched, www.impactjournals.com/Genes&Cancer. Claudin-low, Basal-like, and Normal-like [2, 3, 4], of which, Basal-like type has poor prognosis [5]. Breast cancer is categorized into estrogen receptor (ER)-positive type, progesterone receptor (PgR)positive type, HER2 positive type, and triple-negative type (ER-negative, PgR- negative, HER2-negative) (TNBC). Among 70-80% of Basal-like type of breast cancer has been reported to fall into TNBC category [6]

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