BCL11A enhances stemness and promotes progression by activating Wnt/β-catenin signaling in breast cancer

Lewei Zhu; Ruilin Pan; Dan Zhou; Guolin Ye; Weige Tan

doi:10.2147/CMAR.S199368

BCL11A enhances stemness and promotes progression by activating Wnt/β-catenin signaling in breast cancer

Cancer Manag Res. 2019 Apr 11:11:2997-3007. doi: 10.2147/CMAR.S199368. eCollection 2019.

Authors

Lewei Zhu¹, Ruilin Pan¹, Dan Zhou¹, Guolin Ye¹, Weige Tan²

Affiliations

¹ Department of Breast Surgery, The First People's Hospital, Foshan, Guangdong, People's Republic of China.
² Breast Surgery Department, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, People's Republic of China.

Abstract

Background: Breast cancer has become the most common malignant disease threatening women's health. The cancer stem cell (CSC) has been recognized as a small subpopulation of cancer cells possesses stem cell properties, which is crucial in tumorigenicity, tumor invasion, drug resistance, and metastasis. The BCL11A plays a crucial role in breast cancer progression. To investigate the effect of BCL11A, a functional oncogene, we focused on its maintenance ability of stemness in breast cancer stem cells. Methods: We assessed the BCL11A expression level in tumor and non-tumor tissues using RT-qPCR and IHC. We subsequently established BCL11A-modulating breast cancer cell lines MDA-MB-231 and MCF-7. CCK8, colony formation assays, and xenograft model were used to determine the effect of BCL11A on tumorigenicity. Transwell assay and lung metastasis model in vivo were conducted to validate its function in metastasis. Its effect on stemness was assessed by flow cytometry and mammosphere formation. Western blot further characterized the importance of Wnt/β-catenin signaling in BCL11A-regulated cancer cell stemness. Results: A higher level of BCL11A was detected in clinical breast cancer samples. BCL11A promoted tumor formation, cancer cell mobility, spheroid forming, and epithelial-mesenchymal transition by activating the Wnt/β-catenin signaling. In addition, BCL11A was associated with lung metastasis and increased the breast cancer cells stemness. BCL11A high expression (BCL11A^high) cancer cells exhibited stem cell-like properties compared with BCL11A^low cells, including a higher percentage of CD24^low/CD44^high subpopulation, self-renewal spheroids formation, and higher tumorigenicity. Our studies demonstrated that the Wnt/β-catenin signaling activated by BCL11A plays a potential role in the initiation of the renewal of breast cancer stem cells. Conclusions: BCL11A not only functions in breast cancer carcinogenesis but also enhanced the stemness of breast cancer through activating Wnt/β-catenin signaling, and may become a potential target for breast cancer treatment.

Keywords: BCL11A; CSC; Wnt/β-catenin pathway; breast cancer.