TGFβ/cyclin D1/Smad-mediated inhibition of BMP4 promotes breast cancer stem cell self-renewal activity

Gang Yan; Meiou Dai; Chenjing Zhang; Sophie Poulet; Alaa Moamer; Ni Wang; Julien Boudreault; Suhad Ali; Jean-Jacques Lebrun

doi:10.1038/s41389-021-00310-5

TGFβ/cyclin D1/Smad-mediated inhibition of BMP4 promotes breast cancer stem cell self-renewal activity

Oncogenesis. 2021 Mar 1;10(3):21. doi: 10.1038/s41389-021-00310-5.

Authors

Gang Yan¹, Meiou Dai¹, Chenjing Zhang^{1

2}, Sophie Poulet¹, Alaa Moamer¹, Ni Wang¹, Julien Boudreault¹, Suhad Ali¹, Jean-Jacques Lebrun³

Affiliations

¹ McGill University Health Center, Department of Medicine, Cancer Research Program, Montreal, QC, H4A 3J1, Canada.
² Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China.
³ McGill University Health Center, Department of Medicine, Cancer Research Program, Montreal, QC, H4A 3J1, Canada. JJ.Lebrun@mcgill.ca.

Abstract

Basal-like triple-negative breast cancers (TNBCs) display poor prognosis, have a high risk of tumor recurrence, and exhibit high resistance to drug treatments. The TNBC aggressive features are largely due to the high proportion of cancer stem cells present within these tumors. In this study, we investigated the interplay and networking pathways occurring between TGFβ family ligands in regulating stemness in TNBCs. We found that TGFβ stimulation of TNBCs resulted in enhanced tumorsphere formation efficiency and an increased proportion of the highly tumorigenic CD44^high/CD24^low cancer stem cell population. Analysis of the TGFβ transcriptome in TNBC cells revealed bone morphogenetic protein4 (BMP4) as a main TGFβ-repressed target in these tumor cells. We further found that BMP4 opposed TGFβ effects on stemness and potently decreased cancer stem cell numbers, thereby acting as a differentiation factor in TNBC. At the molecular level, we found that TGFβ inhibition of BMP4 gene expression is mediated through the Smad pathway and cyclin D1. In addition, we also found BMP4 to act as a pro-differentiation factor in normal mammary epithelial cells and promote mammary acinar formation in 3D cell culture assays. Finally, and consistent with our in vitro results, in silico patient data analysis defined BMP4 as a potential valuable prognosis marker for TNBC patients.