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Upregulation of S100A10 in metastasized breast cancer stem cells.

ABSTRACT: Metastatic progression remains the major cause of death in human breast cancer. Cancer cells with cancer stem cell (CSC) properties drive initiation and growth of metastases at distant sites. We have previously established the breast cancer patient-derived tumor xenograft (PDX) mouse model in which CSC marker CD44⁺ cancer cells formed spontaneous microscopic metastases in the liver. In this PDX mouse, the expression levels of S100A10 and its family proteins were much higher in the CD44⁺ cancer cells metastasized to the liver than those at the primary site. Knockdown of S100A10 in breast cancer cells suppressed and overexpression of S100A10 in breast cancer PDX cells enhanced their invasion abilities and 3D organoid formation capacities in vitro. Mechanistically, S100A10 regulated the matrix metalloproteinase activity and the expression levels of stem cell-related genes. Finally, constitutive knockdown of S100A10 significantly reduced their metastatic ability to the liver in vivo. These findings suggest that S100A10 functions as a metastasis promoter of breast CSCs by conferring both invasion ability and CSC properties in breast cancers.

SUBMITTER: Yanagi H

PROVIDER: S-EPMC7734155 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Upregulation of S100A10 in metastasized breast cancer stem cells.

Yanagi Hisano H Watanabe Takashi T Nishimura Tatsunori T Hayashi Takanori T Kono Seishi S Tsuchida Hitomi H Hirata Munetsugu M Kijima Yuko Y Takao Shintaro S Okada Seiji S Suzuki Motoshi M Imaizumi Kazuyoshi K Kawada Kenji K Minami Hironobu H Gotoh Noriko N Shimono Yohei Y

Cancer science 20201011 12

Metastatic progression remains the major cause of death in human breast cancer. Cancer cells with cancer stem cell (CSC) properties drive initiation and growth of metastases at distant sites. We have previously established the breast cancer patient-derived tumor xenograft (PDX) mouse model in which CSC marker CD44<sup>+</sup> cancer cells formed spontaneous microscopic metastases in the liver. In this PDX mouse, the expression levels of S100A10 and its family proteins were much higher in the CD4 ...[more]

PMID: 32976661

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Project description:BACKGROUND:Breast adipocytes play important roles in both the development and function of mammary epithelial cells. Therefore, carcinoma-adipose stromal cell (ASC) interactions have been considered pivotal in supporting tumor growth in breast cancer. In addition, it has been demonstrated that the biological features of cancer-associated adipocytes differ from those of normal ASCs. Therefore, we investigated an interaction between ASCs and carcinoma cell lines to identify genes associated with ASC invasion of carcinoma cells. METHODS:3T3-L1 ASC-derived conditioned medium (CM) was treated to measure the proliferation rate of breast cancer cells. To further examine the effect of ASCs, breast cancer cells were cocultivated with either primary human or 3T3-L1 ASCs for migration assays, DNA microarrays, quantitative real-time polymerase chain reactions, and Western blotting experiments. Furthermore, immunoreactivity of S100A7, the most upregulated gene in MCF7, after coculture with ASCs was evaluated for 150 breast cancer tissues to statistically analyze its association with clinicopathological parameters. RESULTS:We first confirmed that ASC-derived CM treatment enhanced the cell proliferation rate of MCF7, T47D, SK-BR-3, and ZR-75-1 cell lines, whereas the migration rate of breast cancer cells was promoted by coculture with ASCs. We identified that a small calcium-binding protein, S100A7, was markedly upregulated (by 5.8-fold) in MCF7 cells after coculture with primary human ASCs. Knockdown of S100A7 significantly suppressed ASC-stimulated cell proliferation and migration rate, indicating a possible involvement of S100A7 in the carcinoma-ASC interaction in breast tumors. Furthermore, strong S100A7 immunoreactivity was detected at the invasive front of adipose stromal tissues compared with that at the intratumoral area. The status of S100A7 was also significantly correlated with adverse pathological parameters, and multivariate analysis revealed that S100A7 could be an independent prognostic marker for a poor relapse-free survival rate. Moreover, induction of oncostatin M was detected in cancer-stimulated ASCs, whereas the downstream S100A7 binding proteins/receptor for advanced glycation endproducts were significantly upregulated in correspondence with S100A7 expression in breast cancer cells after coculture with ASCs. CONCLUSIONS:The results of our study suggest that paracrine production of cytokines from ASCs stimulates breast carcinoma cell growth via upregulation of S100A7 expression in breast cancer cell lines.

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Upregulation of S100A10 in metastasized breast cancer stem cells.

Publications

Upregulation of S100A10 in metastasized breast cancer stem cells.

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