Tumor metastasis remains the main cause of breast cancer-related deaths, especially delayed breast cancer distant metastasis. The current study assessed the frequency of CD44-/CD24- breast cancer cells in 576 tissue specimens for associations with clinicopathological features and metastasis and investigated the underlying molecular mechanisms. The results indicated that higher frequency (≥19.5%) of CD44-/CD24- cells was associated with delayed postoperative breast cancer metastasis. Furthermore, CD44-/CD24- triple negative breast cancer (TNBC) cells spontaneously converted into CD44+/CD24- cancer stem cells (CSCs) with properties similar to CD44+/CD24- CSCs from primary human breast cancer cells and parental TNBC cells in terms of stemness marker expression, self-renewal, differentiation, tumorigenicity and lung metastasis in vitro and in NOD/SCID mice. RNA sequencing identified several differentially expressed genes (DEGs) in newly converted CSCs and RHBDL2, one of the DEGs, expression was up-regulated. More importantly, RHBDL2 silencing inhibited the YAP1/USP31/NF-κB signaling and attenuated spontaneous CD44-/CD24- cell conversion into CSCs and their mammosphere formation. These findings suggest that the frequency of CD44-/CD24- tumor cells and RHBDL2 may be valuable for prognosis of delayed breast cancer metastasis, particularly for TNBC.
All data generated or analysed during this study are included in the manuscript and supporting files.
- Caigang Liu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: The experimental protocol was approved by the Animal Research and Care Committee of China Medical University (Shenyang, China) and followed the Guidelines of the Care and Use of Laboratory Animals issued by the Chinese Council on Animal Research. Female BALB/c nude mice (6 weeks old) were obtained from Human Silaikejingda Laboratory Animals (Changsha, China) and housed in a specific pathogen-free facility with free access to autoclaved food and water. All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering. The current study was approved by the Ethics Committee of all three hospital review board review boards ((Project identification code: Project identification code: 2018PS304K, date on 03/05/2018 2018PS304K, date on 03/05/2018))
- Renata Pasqualini, Rutgers University, United States
© 2021, Qiao et al.
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