Association of human breast cancer CD44-/CD24- cells with delayed distant metastasis
Xinbo Qiao, Yixiao Zhang, Lisha Sun, Qingtian Ma, Jie Yang, Liping Ai, Jinqi Xue, Guanglei Chen, Hao Zhang, Ce Ji, Xi Gu, Haixin Lei, Yongliang Yang, Caigang Liu
Abstract
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 upregulated. 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.