Breast cancer represents a major threat of women health. Due to high heterogeneity, most cancer therapies are often defeated by a minor subpopulation of cancer cells with enhanced therapy resistance, named cancer stem-like cells (CSCs), which leads to tumor recurrence and eventually therapy failure.  

Currently, two populations of breast cancer stem-like cells (BCSCs) characterized by CD44⁺ CD24^low/- and high aldehyde dehydrogenase (ALDH), respectively, were identified. Although a number of studies have identified the intracellular and microenvironmental cues that regulate breast cancer stemness, understanding towards CSCs in breast cancer remains incomplete. Elucidating the molecular underpinning of BCSCs, especially the common regulators of different BCSC types with clinical relevance, will be important for rational designing of new CSC-targeting strategies in cancer treatment.  

A research group led by Dr. HU Guohong from Shanghai Institute of Nutrition and Health (SINH) of Chinese Academy of Sciences reveals that SH3 domain containing ring finger 3 (SH3RF3), a scaffold protein, promotes cancer stem-like properties of breast cancer by activating JNK-JUN pathway and PTX3 upregulation.   

This study showed that overexpression of SH3RF3 in breast cancer cells expands the CD44⁺CD24^low/- and ALDH⁺ cell population of breast cancer cells, accompanied by increase of tumorsphere formation in vitro and tumorigenicity in vivo. The function of SH3RF3 on tumor stem-like properties facilitation was also confirmed by the culturing of breast cancer patient-derived organoids. Mechanistically, SH3RF3 interacts with the MKK-JNK complex, leading to enhanced phosphorylation of JNK and activation of the JNK-JUN pathway in a JIP-dependent manner. Further, the JNK-JUN signaling expands CSC subpopulation by transcriptionally activating the expression of Pentraxin 3 (PTX3). Moreover, clinical relevance analysis reveals that the expression of SH3RF3 is positively correlated with BCSC properties in breast cancer samples and predicts poor prognosis.   

Overall, this study elucidates the role of SH3RF3 and JNK-JUN pathway in breast cancer stemness regulation. The findings may provide potential diagnostic biomarkers and therapeutic targets. Entitled “SH3RF3 Promotes Breast Cancer Stem-Like Properties via JNK Activation and PTX3 Upregulation”, this research was published online in Nature Communications on May 19, 2020.   

Dr. HU Guohong is the corresponding author of the article. Dr. LIU Tong, a chief physician of the Cancer Hospital of Harbin Medical University, is the co-corresponding author. Dr. ZHANG Peiyuan and graduate student LIU Yingjie are the co-first authors of the work. The work was also supported by Dr. WEI Gang at SINH. This project was sponsored by the National Natural Science Foundation of China, the Chinese Academy of Sciences and the Shanghai Municipal Science and Technology Commission.  

Schematic model of the role of SH3RF3 in BCSC regulation. (Image provided Dr. HU Guohong's Group) 

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Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: sibssc@sibs.ac.cn