Breast cancer is now the most frequently diagnosed cancer and the leading global cause of cancer death in women. Despite advances in the diagnosis and treatment of human breast cancer, advanced stage, metastatic breast cancers are difficult to cure. Among the common target organs for breast cancer metastasis, post recurrence survival is worst when multiple metastasis was observed in the liver. Cancer stem cells (CSCs) are a sub-population of the cells that retain high tumorigenic capacity and, at the same time, are able to sustain the formation of tumors that recreate the cellular diversity of the parent lesions from which they have been originally isolated. We and others have shown that in epithelial malignancies such as breast and colorectal cancers, self-renewal ability of cancer cells with CSC properties is epigenetically regulated by their expression of microRNAs, such as with miR-200c, miR-142 and miR-221. Because of their highly tumorigenic properties, CSCs with are associated with metastatic progression, especially at the initial steps of metastases. 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. Comparison of gene expression profiles between the CD44+ human breast cancer cells metastasized to the liver (‘metastasized CSCs') and those in the primary site (‘primary CSCs') revealed that S100A10 was upregulated in metastasized CSCs than in primary CSCs. Knockdown of S100A10 in breast cancer cells reduced the matrix metalloproteinase activity and suppressed their invasion abilities in transwell cell invasion assays in which upper surface of transwell inserts were precoated with Matrigel. Knockdown of S100A10 suppressed, and overexpression of S100A10 enhanced the 3D organoid formation capacities of breast cancer PDX cells in vitro. Finally, constitutive knockdown of S100A10 significantly reduced their metastatic ability to the liver in vivo. Upregulation of S100 family protein expression is observed in many human cancers, including breast, lung, bladder and gastric cancers. These findings suggest that S100A10 functions as a metastasis promoter of breast CSCs by conferring both invasion ability and CSC properties in breast cancers.

Citation Format: Yohei Shimono, Hisano Yanagi, Takashi Watanabe, Tatsunori Nishimura, Takanori Hayashi, Seiji Okada, Motoshi Suzuki, Kenji Kawada, Hironobu Minami, Noriko Gotoh. Role of S100A10 in the metastatic colonization of breast cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3083.